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1. Micro-RNAs in inflammatory arthritis: From physiopathology to diagnosis, prognosis and therapeutic opportunities

Author

Frédéric Blanchard, Benoit Le Goff, Aurélie Najm, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0301 basic medicine, Inflammatory arthritis, medicine.medical_treatment, T cell, Arthritis, Apoptosis, Inflammation, Biochemistry, Arthritis, Rheumatoid, 03 medical and health sciences, Psoriatic arthritis, 0302 clinical medicine, Cell Movement, Animals, Humans, Immunologic Factors, Medicine, Cell Proliferation, Pharmacology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Prognosis, medicine.disease, Acquired immune system, 3. Good health, MicroRNAs, 030104 developmental biology, Cytokine, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Immunology, Inflammation Mediators, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Micro-RNAs are an area of research exponentially expanding over the past years. These small sequences of 20-22 nucleotides have a strong role as post-transcriptional regulators of gene expression. Inflammatory arthritis pa-thophysiology involves various key players from innate to adaptive immunity, as well as various signalling pathways of inflammation. In this review, we discuss how micro-RNAs are involved in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and juvenile inflammatory arthritis, from pre-clinical phases to established diseases. We describe mi-RNAs key roles in fibroblast like synoviocytes migration, proliferation, apoptosis and cytokine production, in macrophages polarization, as well as in B cells and T cell proliferation and differentiation, with a special emphasis on Treg/Th17 imbalance. We finally discuss the application of these findings in pre-clinical models and highlight opportunities and limits of a therapeutic approach using mi-RNAs agonists or antagonists.

Published
2019
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2. Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

Author

Talbot, Julie, Dupuy, Maryne, Morice, Sarah, Redini, Françoise, Verrecchia, Franck, Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and maurice, sandrine

Subjects
Male, Epithelial-Mesenchymal Transition, lcsh:QR1-502, Gene Expression, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Models, Biological, lcsh:Microbiology, connexin 43, gap junction, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Animals, Humans, metastatic process, Neoplasm Metastasis, primary tumor growth, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, Mice, Knockout, bone tumors, metastatic process 29 30, Gap Junctions, Prostatic Neoplasms, Female, Bone Remodeling
Abstract

International audience; Despite research and clinical advances during the past decades, bone cancers remain 11 a leading cause of death worldwide. There is a low survival rate for patients with primary bone 12 tumors such as osteosarcoma and Ewing's sarcoma or secondary bone tumors such as bone 13 metastases from prostate carcinoma. Gap junctions are specialized plasma membrane 14 structures consisting of transmembrane channels that directly link the cytoplasm of adjacent 15 cells, thereby enabling the direct exchange of small signaling molecules between cells. 16 Discoveries of human genetic disorders due to genetic mutations in gap junction proteins 17 (connexins) and experimental data using connexin knockout mice have provided significant 18 evidence that gap junctional intercellular communication (Gj) is crucial for tissue function. 19 Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is 20 thus a main mechanism for tumor cells to communicate with other tumor cells and their 21 surrounding microenvironment to survive and proliferate. If it is well accepted that a low level 22 of connexin expression favors cancer cell proliferation and therefore primary tumor 23 development, more evidence is suggesting that a high level of connexin expression stimulates 24 various cellular process such as intravasation, extravasation or migration of metastatic cells. If 25 so, connexin expression would facilitate secondary tumor dissemination. This paper discusses 26 evidence that suggests that connexin 43 plays an antagonistic role in the development of 27 primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.

Published
2020
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3. IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

Author

Géraldine Bart, Benoit Le Goff, Pierre Layrolle, Cem Gabay, Frédéric Blanchard, Gaby Palmer, Aurélie Najm, Régis Brion, S Touchais, Valérie Trichet, Marie-Astrid Boutet, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe Labellisée LIGUE 2012 [Nantes], Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Division of Rheumatology [Geneva, Switzerland], Geneva University Hospital, Geneva-Department of Internal Medicine [Genève], This work was supported by Inserm and in part by the Arthritis Foundation and by the French Society of Rheumatology. M-AB was a recipient from a fellowship from the French Ministry of Research. CG is supported by grants from the Swiss National Science Foundation (310030_152638), the Rheumasearch Foundation, the Uniscientia Foundation and the Institute of Arthritis Research., maurice, sandrine, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland]

Subjects
Cartilage, Articular, 0301 basic medicine, medicine.medical_treatment, Arthritis, Macrophages/immunology, Interleukin-23, Arthritis, Rheumatoid, Mice, 0302 clinical medicine, Tumor Necrosis Factor-alpha/genetics/immunology, Immunology and Allergy, ddc:616, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Interleukin-17, Synovial Membrane, Interleukin, Arthritis, Experimental/genetics/immunology, Immunohistochemistry, Interleukin-17/genetics/immunology, 3. Good health, Synovial Membrane/cytology, medicine.anatomical_structure, Cytokine, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Cytokines, Tumor necrosis factor alpha, Arthritis, Rheumatoid/immunology, Blotting, Western, Immunology, Enzyme-Linked Immunosorbent Assay, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, In Vitro Techniques, Real-Time Polymerase Chain Reaction, Bone and Bones, Interleukin-6/genetics/immunology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Proinflammatory cytokine, 03 medical and health sciences, Rheumatology, Fibroblasts/immunology, medicine, Animals, Humans, Th17 Cells/immunology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Inflammation, Interleukin-6, Tumor Necrosis Factor-alpha, business.industry, Interleukins, Macrophages, Cartilage, Bone and Bones/diagnostic imaging, X-Ray Microtomography, Fibroblasts, Interleukins/genetics/immunology, medicine.disease, Arthritis, Experimental, Cartilage, Articular/diagnostic imaging, 030104 developmental biology, Interleukin-23/genetics/immunology, Cell culture, Culture Media, Conditioned, Th17 Cells, Transcriptome, business
Abstract

International audience; OBJECTIVES:Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.METHODS:Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38.RESULTS:Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA.CONCLUSIONS:This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.

Published
2017
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4. Bone regeneration strategies with bone marrow stromal cells in orthopaedic surgery

Author

Pierre Layrolle, Luciano Vidal, Julien Stanovici, L.-R. Le Nail, Meadhbh Á. Brennan, Valérie Trichet, Philippe Rosset, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de chirurgie orthopédique et reconstructive pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), European Project: 241879,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,REBORNE(2010), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), maurice, sandrine, and Regenerating Bone defects using New biomedical Engineering approaches - REBORNE - - EC:FP7:HEALTH2010-01-01 - 2015-06-30 - 241879 - VALID

Subjects
Calcium Phosphates, 0301 basic medicine, Bone Regeneration, [SDV]Life Sciences [q-bio], Orthopaedic surgery, Osteoporosis, Cell Separation, Injections, Intralesional, Cell therapy, Femur Head Necrosis, Concentrated bone marrow, Cells, Cultured, Fracture Healing, Bone substitutes, Bone Transplantation, Tissue Scaffolds, Osteonecrosis, General Medicine, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Stem cell, medicine.medical_specialty, Stromal cell, Neovascularization, Physiologic, Bone Marrow Cells, Bone healing, Mesenchymal Stem Cell Transplantation, Transplantation, Autologous, Bone and Bones, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Bone regeneration, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Mesenchymal stromal stem cells, business.industry, Regeneration (biology), Mesenchymal stem cell, Mesenchymal Stem Cells, medicine.disease, Surgery, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, Non-union fractures, Durapatite, 030104 developmental biology, Fractures, Ununited, Bone marrow, business, Forecasting
Abstract

International audience; Bone is the most transplanted tissue human with 1 million procedures every year in Europe. Surgical interventions for bone repair are required for varied reasons such as trauma resulting non-union fractures, or diseases including osteoporosis or osteonecrosis. Autologous bone grafting is the gold standard in bone regeneration but it requires a second surgery with associated pain and complications, and is also limited by harvested bone quantity. Synthetic bone substitutes lack the osteoinductive properties to heal large bone defects. Cell therapies based on bone marrow or ex vivo expanded mesenchymal stromal stem cells (MSCs) in association with synthetic calcium phosphate (CaP) bone substitutes may be alternatives to autologous bone grafting. This manuscript reviews the different conventional biological and synthetic bone grafting procedures as well as the more recently introduced cell therapy approaches used in orthopaedic surgery for bone regeneration. Some clinical studies have demonstrated safety and efficacy of these approaches but regeneration of large bone defects remain challenging due to the absence of rapid and adequate vascularisation. Future directions in the field of bone regeneration are presented, such as testing alternative cell sources or in situ fabrication of vascularized bone grafts in patients.

Published
2016
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5. Opposite Effects of Soluble Factors Secreted by Adipose Tissue on Proliferating and Quiescent Osteosarcoma Cells

Author

Pierre Avril, Franck Duteille, Perrine Ridel, Marie-Françoise Heymann, Gonzague De Pinieux, Françoise Rédini, Frédéric Blanchard, Dominique Heymann, Valérie Trichet, Pierre Perrot, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe labellisée Ligue contre le Cancer, Service de Chirurgie Plastique et des Brulés [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d’Anatomie et Cytologie Pathologiques [CHU Nantes], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by INSERM, the 'Ligue Contre le Cancer' (Equipe Labellisée LIGUE 2012). Pierre Avril was a recipient of the 'Fédération Nationale Enfants et Santé' and the 'Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’Adolescent.' Perrine Ridel, M.D., was a recipient of 'Institut national du Cancer.', Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and maurice, sandrine

Subjects
0301 basic medicine, Mice, Nude, Bone Neoplasms, Injections, Intralesional, Transplantation, Autologous, Mice, Random Allocation, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Animals, Humans, Cell Proliferation, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Osteosarcoma, Cell Cycle, 3. Good health, Disease Models, Animal, 030104 developmental biology, Adipose Tissue, Solubility, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Culture Media, Conditioned, 030220 oncology & carcinogenesis, Female, Surgery, Neoplasm Recurrence, Local
Abstract

Comment in Discussion: Opposite Effects of Soluble Factors Secreted by Adipose Tissue on Proliferating and Quiescent Osteosarcoma Cells. [Plast Reconstr Surg. 2016]; International audience; BACKGROUND:Autologous adipose tissue transfer may be performed for aesthetic needs following resection of osteosarcoma, the most frequent primary malignant tumor of bone, excluding myeloma. The safety of autologous adipose tissue transfer regarding the potential risk of cancer recurrence must be addressed.METHODS:Adipose tissue injection was tested in a human osteosarcoma preclinical model induced by MNNG-HOS cells. Culture media without growth factors from fetal bovine serum were conditioned with adipose tissue samples and added to two osteosarcoma cell lines (MNNG-HOS and MG-63) that were cultured in monolayer or maintained in nonadherent spheres, favoring a proliferation or quiescent stage, respectively. Proliferation and cell cycle were analyzed.RESULTS:Adipose tissue injection increased local growth of osteosarcoma in mice but was not associated with aggravation of lung metastasis or osteolysis. Adipose tissue-derived soluble factors increased the in vitro proliferation of osteosarcoma cells up to 180 percent. Interleukin-6 and leptin were measured in higher concentrations in adipose tissue-conditioned medium than in osteosarcoma cell-conditioned medium, but the authors' results indicated that they were not implicated alone. Furthermore, adipose tissue-derived soluble factors did not favor a G0-to-G1 phase transition of MNNG-HOS cells in nonadherent oncospheres.CONCLUSIONS:This study indicates that adipose tissue-soluble factors activate osteosarcoma cell cycle from G1 to mitosis phases, but do not promote the transition from quiescent G0 to G1 phases. Autologous adipose tissue transfer may not be involved in the activation of dormant tumor cells or cancer stem cells.

Published
2016
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6. New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies?

Author

Danieau, Geoffroy, Morice, Sarah, Rédini, Françoise, Verrecchia, Franck, Brounais-Le Royer, Benedicte, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
bone tumor microenvironment, Adolescent, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], bone sarcoma, Antineoplastic Agents, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Review, Bone and Bones, lcsh:Chemistry, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tumor Microenvironment, Humans, Molecular Targeted Therapy, Child, lcsh:QH301-705.5, Wnt Signaling Pathway, beta Catenin, Osteosarcoma, Wnt/β-catenin, Neovascularization, Pathologic, Proto-Oncogene Proteins c-ets, Survival Analysis, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], lcsh:Biology (General), lcsh:QD1-999, Lymphatic Metastasis, RNA-Binding Protein EWS
Abstract

International audience; Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/β-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/β-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment. Keywords: Wnt/β-catenin; bone sarcoma; bone tumor microenvironment 1. Primary Bone Tumors: Osteosarcoma and Ewing Sarcoma Osteosarcoma and Ewing sarcoma are the most common primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation for Ewing sarcoma, associated with tumor resection. However, the 5-year survival rates have not been improved during the last decades reaching 70-80% for patients with localized forms, but less than 30% in metastatic diseases and patients resistant to initial chemotherapy [1-5]. Osteosarcoma that mainly occurs at the ends of long bones is not associated with any clinical signs except severe pain or spontaneous fracture. Osteosarcoma does not express specific oncogenic markers but exhibits a large number and variety of genetic alterations. Ewing sarcoma is a tumor composed of small undifferentiated round cells that can appear mainly in bones but also in soft tissues in 15% of Int.

Published
2019
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7. Immune Modulation by Transplanted Calcium Phosphate Biomaterials and Human Mesenchymal Stromal Cells in Bone Regeneration

Author

Paul Humbert, Meadhbh Á. Brennan, Noel Davison, Philippe Rosset, Valérie Trichet, Frédéric Blanchard, Pierre Layrolle, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), Harvard University [Cambridge], MERLN Institute for Technology-Inspired Regenerative Medicine [Maastricht, Netherlands], Instructure Labs B.V. [The Hague, Netherlands], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes), and maurice, sandrine

Subjects
osteoimmunology, Calcium Phosphates, calcium phosphate biomaterial, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, immune modulation, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Bone Regeneration, Immunology, Biocompatible Materials, Mesenchymal Stem Cells, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mesenchymal Stem Cell Transplantation, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Immunomodulation, Osteogenesis, osteoclast, mesenchymal stromal cell, Immunology and Allergy, Animals, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; A wide variety of biomaterials have been developed as both stabilizing structures for the injured bone and inducers of bone neoformation. They differ in chemical composition, shape, porosity, and mechanical properties. The most extensively employed and studied subset of bioceramics are calcium phosphate materials (CaPs). These materials, when transplanted alongside mesenchymal stem cells (MSCs), lead to ectopic (intramuscular and subcutaneous) and orthotopic bone formation in preclinical studies, and effective fracture healing in clinical trials. Human MSC transplantation in pre-clinical and clinical trials reveals very low engraftment in spite of successful clinical outcomes and their therapeutic actions are thought to be primarily through paracrine mechanisms. The beneficial role of transplanted MSC could rely on their strong immunomodulatory effect since, even without long-term engraftment, they have the ability to alter both the innate and adaptive immune response which is critical to facilitate new bone formation. This study presents the current knowledge of the immune response to the implantation of CaP biomaterials alone or in combination with MSC. In particular the central role of monocyte-derived cells, both macrophages and osteoclasts, in MSC-CaP mediated bone formation is emphasized. Biomaterial properties, such as macroporosity and surface microstructure, dictate the host response, and the ultimate bone healing cascade. Understanding intercellular communications throughout the inflammation, its resolution and the bone regeneration phase, is crucial to improve the current therapeutic strategies or develop new approaches.

Published
2018
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8. Bidirectional regulation of bone formation by exogenous and osteosarcoma-derived Sema3A

Author

Ryan T. Bishop, Daniëlle de Ridder, Dominique Heymann, Aymen I. Idris, Chantal Chenu, Silvia Marino, Nathalie Renema, Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Comparative Biomedical Sciences [London, UK], Royal Veterinary College - University of London, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), This work was supported by the Bone Cancer Research Trust PhD grant to Aymen I. Idris., maurice, sandrine, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0301 basic medicine, musculoskeletal diseases, Osteolysis, Science, Osteoclasts, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone healing, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Semaphorin, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Osteogenesis, Cell Line, Tumor, medicine, Animals, Humans, beta Catenin, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Osteosarcoma, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Osteoblasts, Chemistry, Osteoblast, SEMA3A, Semaphorin-3A, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, RAW 264.7 Cells, DKK1, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Intercellular Signaling Peptides and Proteins, Medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract

International audience; Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, increases osteoblast differentiation, stimulates bone formation and enhances fracture healing. Here, we report a previously unknown role of Sema3A in the regulation of ectopic bone formation and osteolysis related to osteosarcoma. Human recombinant (exogenous) Sema3A promoted the expression of osteoblastic phenotype in a panel of human osteosarcoma cell lines and inhibited the ability of these cells to migrate and enhance osteoclastogenesis in vitro. In vivo, administration of exogenous Sema3A in mice after paratibial inoculation of KHOS cells increased bone volume in non-inoculated and tumour-bearing legs. In contrast, Sema3A overexpression reduced the ability of KHOS cells to cause ectopic bone formation in mice and to increase bone nodule formation by engaging DKK1/β-catenin signalling. Thus, Sema3A is of potential therapeutic efficacy in osteosarcoma. However, inhibition of bone formation associated with continuous exposure to Sema3A may limit its long-term usefulness as therapeutic agent. Osteosarcoma is an aggressive form of skeletal cancer, typically with childhood and adolescent onsets 1–3. Metastasis is a serious clinical manifestation of osteosarcoma 4,5. However, skeletal complications such as osteol-ysis and rapid production of ectopic " woven " bone cause skeletal fractures and pain 4,5. Thus, treatments aimed at reducing bone damage and halting metastasis would prove to be beneficial in terms of clinical outcomes and quality of life of osteosarcoma patients. Semaphorins belong to a highly conserved family of secreted and membrane-associated signaling proteins 6,7. Of the 8 different classes, only class 3 semaphorins (Sema3) are secreted 8–10. Type A Sema3 (Sema3A) is synthesized as a precursor protein and proteolytically processed into two active secreted forms of 95 and 65 kilodaltons 8–10. Secreted Sema3A is implicated in the migration of neuronal precursor cells and guided elongation and branching patterns of neurons 11–15. Sema3A, and its co-receptors Neuropilin (Nrp)1 and 2 16–18 , are expressed by a variety of human cancer cells. Engagement of Sema3A with Nrp1 and 2 and other receptors has shown to both enhance and reduce tumour cell motility and invasion in various preclinical models of cancer 19–24. Recent studies have reported that osteosarcoma tumours and cell lines overexpress both Nrp1 and Nrp2. Furthermore, Nrp2 expression is associated with poor prognosis and reduced overall survival in osteosarcoma patients 25–27 , and its knockdown in the human osteosarcoma cell line 143B inhibited tumour growth and reduced lung metastasis in mice 27. The Sema3A/Nrp axis plays a key role in the regulation of bone development and remodelling 28–30. Sema3A, Nrp1/2 and Plexin-A1 are highly expressed in hypertrophic chondrocytes during embryonic development and in blood vessels and nerves at later stages of bone development 31. Nrp1 and Nrp2 are expressed by osteoblasts and osteocytes, and mice deficient in Nrp2 exhibited bone loss due to enhanced osteoclast and reduced oste-oblast numbers 32. Recently, Hayashi and colleagues have reported that osteoblasts secrete Sema3A, and adult mice deficient in Sema3A had low peak bone mass mainly due to enhanced bone resorption and reduced osteo-blast differentiation 29,32. Furthermore, administration of Sema3A in mice enhanced osteoblast differentiation and bone formation, promoted fracture healing in osteoporotic rats and protected against bone loss due to oestrogen deficiency 29,31,33 .

Published
2018
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9. Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial

Author

Hubert Schrezenmeier, Pierre Layrolle, Harald Gjengedal, Annika Rosén, Xie-Qi Shi, Kamal Mustafa, Xin Feng, Siren Skaale, Sølve Hellem, Bjørn Tore Gjertsen, Trond Inge Berge, Markus Rojewski, Mohammed A. Yassin, Cecilie Gudveig Gjerde, Aymen Bushra Ahmed, Institute of Clinical Dentistry [Bergen, Norway], University of Bergen (UiB), Institute for Clinical Transfusion Medicine and Immunogenetics [Ulm, Germany], German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen, Institute of Transfusion Medicine [Ulm, Germany], Universität Ulm - Ulm University [Ulm, Allemagne], Department of Fibre and Polymer Technology [Stockholm, Sweden], Royal Institute of Technology [Stockholm] (KTH ), Department of Clinical Science [Bergen, Norway] (Section for Hematology ), Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB), Department of Clinical Science [Bergen, Norway] (Precision Oncology Research Group), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), The financial support of the European Union’s Seventh Framework Programme under grant agreement number 241879—REBORNE is acknowledged. The authors also acknowledge the significant contribution by Institut Straumann AG (Basel, Switzerland) for providing the dental implants, Osteogenics Biomedical (Lubbock, TX, USA for the Cytoplast polytetrafluoroethylene membranes, an Ostell (Gothenburg, Sweden) for the Ostell device., maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0301 basic medicine, Male, Bone Regeneration, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, medicine.medical_treatment, Alveolar Bone Loss, Cell- and Tissue-Based Therapy, Medicine (miscellaneous), Dentistry, Biphasic calcium phosphate, Bone tissue engineering, 0302 clinical medicine, lcsh:QD415-436, Alveolar ridge augmentation, Dental implant, Aged, 80 and over, lcsh:R5-920, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Bone Transplantation, Alveolar Ridge Augmentation, Middle Aged, 3. Good health, Resorption, medicine.anatomical_structure, Molecular Medicine, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, Hydroxyapatites, lcsh:Medicine (General), Adult, Adolescent, Bone Marrow Cells, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Biochemistry, Genetics and Molecular Biology (miscellaneous), lcsh:Biochemistry, 03 medical and health sciences, Young Adult, Alveolar ridge, medicine, Humans, Bone regeneration, Aged, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Dental Implants, Wound Healing, Tissue Engineering, business.industry, Research, Mesenchymal stem cell, Mesenchymal Stem Cells, 030206 dentistry, Cell Biology, 030104 developmental biology, Implant, Bone marrow, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Autologous grafting, despite some disadvantages, is still considered the gold standard for reconstruction of maxillofacial bone defects. The aim of this study was to evaluate bone regeneration using bone marrow-derived mesenchymal stromal cells (MSCs) in a clinical trial, a less invasive approach than autologous bone grafting. This comprehensive clinical trial included subjects with severe mandibular ridge resorption. Methods The study included 11 subjects aged 52–79 years with severe mandibular ridge resorption. Bone marrow cells were aspirated from the posterior iliac crest and plastic adherent cells were expanded in culture medium containing human platelet lysate. The MSCs and biphasic calcium phosphate granules as scaffolds were inserted subperiosteally onto the resorbed alveolar ridge. After 4–6 months of healing, new bone formation was assessed clinically and radiographically, as were safety and feasibility. Bone at the implant site was biopsied for micro-computed topography and histological analyses and dental implants were placed in the newly regenerated bone. Functional outcomes and patient satisfaction were assessed after 12 months. Results The bone marrow cells, expanded in vitro and inserted into the defect together with biphasic calcium phosphate granules, induced significant new bone formation. The regenerated bone volume was adequate for dental implant installation. Healing was uneventful, without adverse events. The patients were satisfied with the esthetic and functional outcomes. No side effects were observed. Conclusions The results of this comprehensive clinical trial in human subjects confirm that MSCs can successfully induce significant formation of new bone, with no untoward sequelae. Hence, this novel augmentation procedure warrants further investigation and may form the basis of a valid treatment protocol, challenging the current gold standard. Trial registration EudraCT, 2012-003139-50. Registered on 21 August 2013. ClinicalTrials.gov, NCT 02751125. Registered on 26 April 2016.

Published
2018
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10. In vitro and in vivo discrepancy in inducing apoptosis by mesenchymal stromal cells delivering membrane-bound tumor necrosis factor-related apoptosis inducing ligand in osteosarcoma pre-clinical models

Author

Romain Guiho, Régis Brion, Dominique Heymann, Sarah Renault, Mathias Chatelais, Massimo Dominici, Giulia Grisendi, Françoise Rédini, Kevin Biteau, Julien Taurelle, maurice, sandrine, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Birth Defects Research Centre [London, UK] (Developmental Biology and Cancer Programme), University College of London [London] (UCL)-UCL Great Ormond Street Institute of Child Health [London, UK], Department of Medical and Surgical Sciences for Children and Adults [Modena, Italy] (Laboratory of Cellular Therapy), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Hétérogénéité Tumorale et Médecine de Précision [Saint-Herblain] (Site René Gauducheau), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), This study received funding from la Ligue Contre le Cancer. In addition, this project was carried out with thanks to the support of the Fédération Enfants et Santé and the Société Française de Lutte Contre les Cancers et les Leucémies de L'enfant et de L'adolescent. This project was conducted with financial support from the association Étoile de Martin (R.G.).This work was supported in part by the following: the Associazione Italiana Ricerca Cancro (AIRC) IG 2012 Grant number 12755 (M.D.), the Ministero Italiano Istruzione Università e Ricerca PRIN 2008WECX78 (M.D.), the Ministero della Salute Bando GR-2008-1145964 (MD), and the Associazione ASEOP (M.D. and G.G.)., Università degli Studi di Modena e Reggio Emilia (UNIMORE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
0301 basic medicine, Tumor necrosis factor (TNF)-Related Apoptosis Inducing Ligand, Cancer Research, medicine.medical_treatment, Apoptosis, TNF-Related Apoptosis-Inducing Ligand, Mice, 0302 clinical medicine, Immunology and Allergy, Genetics (clinical), Cells, Cultured, Osteosarcoma, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Transfection, Adoptive Transfer, 3. Good health, Tumor necrosis factor (TNF)–Related Apoptosis Inducing Ligand, Cytokine, Oncology, 030220 oncology & carcinogenesis, mesenchymal stromal cells, osteosarcoma, Immunology, Cell Biology, Transplantation, Tumor necrosis factor alpha, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Neoplasms, In Vitro Techniques, Mesenchymal Stem Cell Transplantation, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Humans, business.industry, Mesenchymal stem cell, Mesenchymal Stem Cells, Genetic Therapy, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Tumor progression, Cell culture, Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; In vitro and in vivo discrepancy in inducing apoptosis by mesenchymal stromal cells delivering membrane-bound tumor necrosis factorÀrelated apoptosis inducing ligand in osteosarcoma pre-clinical models Abstract Background: Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor. OS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine Tumor necrosis factor (TNF)ÀRelated Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, many OS cell lines appear resistant to recombinant human (rh)TRAIL-induced apoptosis. We, therefore, hypothesized that TRAIL presentation at the membrane level of carrier cells might overcome this resistance and trigger apoptosis. Methods: To address this, human adipose mesenchymal stromal cells (MSCs) transfected in a stable manner to express membrane-bound full-length human TRAIL (mbTRAIL) were co-cultured with several human OS cell lines. Results: This induced apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL. In contrast, mbTRAIL delivered by MSCs was not able to counteract tumor progression in this OS orthotopic model. Discussion: This was partly due to the fact that MSCs showed a potential to support tumor development. Moreover, the expression of mbTRAIL did not show caspase activation in adjacent tumor cells.

Published
2018
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11. Identification of genomic differences among peripheral arterial beds in atherosclerotic and healthy arteries

Author

Steenman, Marja, Espitia, Olivier, Maurel, Blandine, Guyomarch, Beatrice, Heymann, Marie-Françoise, Pistorius, Marc-Antoine, Ory, Benjamin, Heymann, Dominique, Houlgatte, Rémi, Gouëffic, Yann, Quillard, Thibaut, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de chirurgie vasculaire [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Délégation à la Recherche Clinique et à l'Innovation [CHRU Nancy] (DRCI), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), This work was funded by an Allocation Nationale de Recherche (ANR) for physiopathology and by an inter-regional Programme Hospitalier de Recherche Clinique (PHRC). T. Quillard received financial support from the European commission (Marie Sklodowska-Curie Actions, Individual Fellowships), the Fondation de l’Avenir (Paris, France), the University Hospital of Nantes (CHU Nantes, Nantes, France), and the Fédération Francaise de Cardiologie (Paris, France)., maurice, sandrine, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
Male, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Genome, Human, Gene Expression Profiling, lcsh:R, Calcinosis, lcsh:Medicine, Arteries, Middle Aged, Atherosclerosis, Article, Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Case-Control Studies, Humans, Female, lcsh:Q, lcsh:Science, Aged
Abstract

International audience; Calcification is independently associated with cardiovascular events and morbidity. The calcification burden in atherosclerotic lesions quantitatively and qualitatively differs between arterial beds. Cardiovascular risk factors (CVRF) differentially affect plaque development between arterial beds. The aim of this study was to evaluate the impact of CVRF on atherosclerotic plaque calcification and to further study the molecular arterial heterogeneity that could account for these differences. Histological analysis was performed on atherosclerotic plaques from 153 carotid, 97 femoral and 28 infrapopliteal arteries. CVRF showed minor associations with plaque calcification: age and hypertension affected only the overall presence of calcification but not the type of the calcification, which significantly differed between arterial beds. Transcriptome analysis revealed distinct gene expression profiles associated with each territory in atherosclerotic and healthy arteries. Canonical pathway analysis showed the preferential involvement of immune system-related processes in both atherosclerotic and healthy carotid arteries. Bone development-related genes were among those mostly enriched in atherosclerotic and healthy femoral arteries, which are more prone to developing endochondral calcification. This study highlights the heterogeneous nature of arteries from different peripheral vascular beds and contributes to a better understanding of atherosclerosis formation and evolution. Vascular calcification is an independent predicting factor for cardiovascular events and morbidity 1. Vascular calcification is associated with a worse prognosis after lower limb artery endovascular revascularization: multi-variate analysis reported that the percentage of calcified plaque is an independent predictor of binary restenosis at 12 months 2. Vascular calcification favors plaque rupture and contributes to hypertension depending on its localization and extent. Anatomo-histological studies have shown that atherosclerotic plaque compositions largely differ between anatomical locations in peripheral arterial diseases (PAD). Plaque calcifications are heterogeneous with various types of calcifications, including predominantly microcalcifications in carotid arteries (CA) and bone tissue (osteoid metaplasia) in femoral arteries (FA) 3,4. These differences do not derive from distinct stages of plaque progression , as femoral plaques tend to develop later than those in CA 5. The discrepancies in calcification burden could therefore derive from different shear stress conditions 6 , intrinsic biological differences between vascular cells as suggested by their diverse embryological origins 7,8 , or exposure to different cardiovascular risk factors (CVRF), as CVRF also differentially affect plaque development differentially between arterial beds 9–12 .

Published
2018
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12. Comparison of Tumor- and Bone Marrow-Derived Mesenchymal Stromal/Stem Cells from Patients with High-Grade Osteosarcoma

Author

Le Nail, Louis-Romée, Brennan, Meadhbh, Rosset, Philippe, Deschaseaux, Frédéric, Piloquet, Philippe, Pichon, Olivier, Le Caignec, Cédric, Crenn, Vincent, Layrolle, Pierre, Hérault, Olivier, De Pinieux, Gonzague, Trichet, Valérie, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Service de Chirurgie Orthopédique 2 [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT), Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), Harvard University [Cambridge], STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Chirurgie Orthopédique [CHU Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CNRS GDR 3697 MicroNiT, Centre National de la Recherche Scientifique (CNRS), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by INSERM, by Societe Française de Chirurgie Orthopedique et Traumatologique (SoFCOT), and by Cancéropole Grand Ouest (Penica project)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Université de Tours, Université de Tours-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), maurice, sandrine, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes] (INSERM U1238), Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Harvard School of Engineering and Applied Sciences (SEAS), GICC EA 7501, LNOx (Niche leucémique et métabolisme redOx) (LNOx), Centre National de la Recherche Scientifique (CNRS)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours-Université de Tours, Service d'Anatomie et Cytologie Pathologiques [CHRU Tours], and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP]

Subjects
Adult, Male, cancer stem cells, Adolescent, Karyotype, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, Immunophenotyping, lcsh:Chemistry, Young Adult, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bone Marrow, Cell Line, Tumor, osteosarcoma, Tumor Microenvironment, Humans, Neoplasm Metastasis, spheres, lcsh:QH301-705.5, Cells, Cultured, Neoplasm Staging, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, mesenchymal stem cells, Coculture Techniques, lcsh:Biology (General), lcsh:QD1-999, Neoplastic Stem Cells, Female, Neoplasm Grading, Biomarkers
Abstract

International audience; Osteosarcoma (OS) is suspected to originate from dysfunctional mesenchymal stromal/stem cells (MSC). We sought to identify OS-derived cells (OSDC) with potential cancer stem cell (CSC) properties by comparing OSDC to MSC derived from bone marrow of patients. This study included in vitro characterization with sphere forming assays, differentiation assays, cytogenetic analysis, and in vivo investigations of their tumorigenicity and tumor supportive capacities. Primary cell lines were isolated from nine high-grade OS samples. All primary cell lines demonstrated stromal cell characteristics. Compared to MSC, OSDC presented a higher ability to form sphere clones, indicating a potential CSC phenotype, and were more efficient at differentiation towards osteoblasts. None of the OSDC displayed the complex chromosome rearrangements typical of high grade OS and none of them induced tumors in immunodeficient mice. However, two OSDC demonstrated focused genomic abnormalities. Three out of seven, and six out of seven OSDC showed a supportive role on local tumor development, and on metastatic progression to the lungs, respectively, when co-injected with OS cells in nude mice. The observation of OS-associated stromal cells with rare genetic abnormalities and with the capacity to sustain tumor progression may have implications for future tumor treatments.

Published
2018
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13. 3D curved multiplanar cone beam CT reconstruction for intracochlear position assessment of straight electrodes array. A temporal bone and clinical study

Author

De Seta D, Patrizia Mancini, Fy, Russo, Torres R, Mosnier I, Jl, Bensimon, De Seta E, Heymann D, Sterkers O, Bernardeschi D, Nguyen Y, maurice, sandrine, Réhabilitation Chirurgicale mini-Invasive et Robotisée de l'Audition, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Sense Organs [Rome, Italy], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Histology, Temporal bone, Otology, Imaging, Three-Dimensional, bone regeneration, otorhinolaryngologic diseases, Cadaver, Humans, Electrodes, Retrospective Studies, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cone Beam CT, clectrode position, surface characteristics, hydroxyapatite, Cone-Beam Computed Tomography, Cochlear Implantation, Electrode position, osteoconduction, Cochlear Implants, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Surgery, Computer-Assisted, cochlear implants, cone beam ct, histology, temporal bone, sense organs, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, psychological phenomena and processes
Abstract

Aims: The primary objective of this study was to compare the in vivo performance, namely in terms of quantity of newly formed bone and bone-to-material contact (osteoconductivity), of three hydroxyapatite-based biomaterials (HA) of different origins (natural or synthetic) or manufacturing process in a sinus lift model in rabbits. The secondary objective was to correlate the findings with the physical and topographical characteristics of the biomaterials. Materials and Methods: Two bovine HA manufactured with different processes (bovine hydroxyapatites [BHA] and cuttlebone hydroxyapatite [CBHA]) and a synthetic hydroxyapatite (SHA) sintered at high temperature were characterised with scanning electronic microscopy (SEM) and the measurement of specific surface area (BET). The materials were implanted in a sinus lift model in rabbits; histological and histomorphometric evaluation using non-decalcified sections was performed at 1, 5 and 12 weeks after implantation. Results: The studied biomaterials displayed a different surface topography. The two natural HA displayed significantly higher bone quantities (P = 0.0017; BHA vs. SHA, P = 0.0018 and CBHA vs. SHA, P = 0.033) at 5 and 12 weeks compared to the synthetic one (SHA). Moreover, the osteoconductivity (bone-to-material contact) was significantly higher in the BHA group compared to the two other groups (P = 0.014; BHA vs. SHA, P = 0.023 and BHA vs. CBHA, P = 0.033). Conclusion: HA-based biomaterials from diverse origins and manufacturing processes displayed different topographical characteristics. This may have influenced different regenerated bone architecture observed; more bone was found with natural HA compared to the synthetic one, and significantly higher bone-to-material contacts were found with BHA., Otology 3D curved multiplanar cone beam CT reconstruction for intracochlear position assessment of straight electrodes array. A temporal bone and clinical study Ricostruzione multiplanare 3D di immagini cone beam per l'idenficazione della posizione degli impianti cocleari. Studio su ossi temporali e pazienti impiantati SUMMARY A retrospective review of post-op cone beam CT (CBCT) of 8 adult patients and 14 fresh temporal bones that underwent cochlear implantation with straight flexible electrodes array was performed to determine if the position of a long and flexible electrodes array within the cochlear scalae could be reliably assessed with CBCT. An oto-radiologist and two otologists examined the images and assessed the electrodes position. The temporal bone specimens underwent histological analysis for confirm the exact position. The position of the electrodes was rated as scala tympani, scala vestibule, or intermediate position for the electrodes at 180°, 360° and for the apical electrode. In the patient group, for the electrodes at 180° all observers agreed for scala tympani position except for 1 evaluation, while a discrepancy in 3 patients both for the 360° and for the apical electrode assessment were found. In five temporal bones the evaluations were in discrepancy for the 180° electrode, while at 360° a disagreement between raters on the scalar positioning was seen in six temporal bones. A higher discrepancy between was found in assessment of the scalar position of the apical electrode (average pairwise agreement 45.4%, Fleiss k = 0.13). A good concordance was found between the histological results and the consensus between raters for the electrodes in the basal turn, while low agreement (Cohen's k 0.31, pairwise agreement 50%) was found in the identification of the apical electrode position confirming the difficulty to correct identify the electrode position in the second cochlear turn in temporal bones. In conclusion, CBCT is a reliable radiologic exam to correctly evaluate the position of a lateral wall flexible array in implanted patients using the proposed imaging reconstruction method, while some artefacts impede exact evaluation of the position of the apical electrode in temporal bone and other radiological techniques should be preferred in ex vivo studies. KEY WORDS: Cone Beam CT • Cochlear implants • Electrode position • Histology • Temporal bone RIASSUNTO Questo studio riporta un'analisi retrospettica delle immagini cone beam CT effettuate su 8 pazienti adulti sottoposti ad impianto cochleare MedEl flex 28 e su 14 ossi temporali impiantati con lo stesso tipo di array portaelettrodi. Lo scopo dello studio é di determinare l'affidabilità della metodica cone beam CT nella valutazione della posizione intracocleare degli elettrodi in impianti che si posizionano lungo la parete laterale del lume co-cleare, quindi non perimodiolari la cui posizione é più facilmente identificabile. Un otoradiologo e due otologi hanno analizzato le immagini e as-segnato la posizione per ciascun elettrodo localizzato nella regione dei 180° e dei 360° del primo giro cocleare e per l'elettrodo apicale scegliendo tra scala timpanica, vestibulare o posizione intermedia L'analisi istologica ha successivamente confermato l'esatta posizione negli ossi temporali. Nel gruppo dei pazienti per l'elettrodo a 180° i tre esperti concordavano sulla posizione in scala timpanica in tutti eccetto un paziente, mentre una discordanza nella valutazione era presente in 3 pazienti per gli elettrodi a 360° e per gli elettrodi apicali. Negli ossi temporali in 5 casi era presente una discordanza per l'elettrodo a 180°, mentre a 360° sei valutazioni erano discordanti tra i valutatori. Una disdcordanza tra le valutazioni più elevata veniva trovata per la la posizione dell'elettrodo apicale (concordanza valutatori 45.4%, Fleiss k = 0,13). Un buon grado di concordanza veniva trovato tra i risultati istologici e le valutazioni tra i valutatori per gli elettrodi localizzati nel giro basale; un grado più basso esisteva per la posizione degli elettrodi apicali (concordanza valutatori 50%, Cohen's k = 0,31) confermando la difficoltà nella corretta valutazione della posizione degli elettrodi nella regione più apicale negli ossi temporali. In conclusione, le immagini cone beam postoperatorie analizzate con la metodica della ricostruzione multiplanare 3D rappresentano una metodica affidabile per lo studio della posizione intracocleare degli elettrodi a posizionamento laterale nei pazienti impiantati. La corretta identificazione del posizionamento dell'elettrodo piu apicale risulta difficile su osso temporale per la presenza di un artefatto più importante o per la minore resistenza delle strutture della parete laterale della coclea (legamento spirale, membrane basilare) nel preparato istologico (osso temporale fresco/congelato) che è responsabile di un maggior numero di traslocazioni dalla rampa timpa-nica alla rampa vestibolare e di localizzazioni intermedie più difficilmente interpretabili.

Published
2016
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14. Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification

Author

Espitia, Olivier, Chatelais, Mathias, Steenman, Marja, Charrier, Céline, Maurel, Blandine, Georges, Steven, Houlgatte, Rémi, Verrecchia, Franck, Ory, Benjamin, Lamoureux, François, Heymann, Dominique, Gouëffic, Yann, Quillard, Thibaut, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôtel-Dieu de Nantes, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Délégation à la Recherche Clinique et à l'Innovation [CHRU Nancy] (DRCI), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Programme Hospitalier de Recherche Clinique (PROG/11/58) to YG. The Fondation de l'Avenir pour la Recherche Médicale Appliquée (ET4-720, http://www.fondationdelavenir.org/) to TQ, the Centre Hospitalier Universitaire de Nantes to TQ, and the Agence Nationale de la Recherche (ANR-16-CE14-0012-01, www.agence-nationale-recherche.fr) to BO. Thibaut Quillard's salary has been provided by the Fondation Lefoulon Delalande (http://lefoulon-delalande.institut-de-france.fr/), the European commission (FP7 People: Marie-Curie Actions, grant 627418, https://ec.europa.eu/research/mariecurieactions/), and the Centre Hospitalier Universitaire de Nantes. Steven George's salary has been provided by the Agence Nationale de la Recherche (ANR-16-CE14-0012-01, www.agence-nationale-recherche.fr)., ANR-16-CE14-0012,EPIBONE,Rôle des protéines à bromodomaines dans la physiologie osseuse normale(2016), European Project: 627418,EC:FP7:PEOPLE,FP7-PEOPLE-2013-IIF,CALTHERO(2014), maurice, sandrine, Comparative Study And Mechanisms Of Calcification Heterogeneity In Atherosclerotic Plaques - CALTHERO - - EC:FP7:PEOPLE2014-07-01 - 2016-06-30 - 627418 - VALID, Hôpital Hôtel-Dieu [Nantes] (Centre Hospitalier Universitaire de Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cell biology, Cell signaling, Physiology, Immune Cells, Immunology, lcsh:Medicine, Signal transduction, Muscle, Smooth, Vascular, Calcification, White Blood Cells, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Animal Cells, Medicine and Health Sciences, Genetics, Humans, lcsh:Science, Aorta, Cells, Cultured, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Blood Cells, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Macrophages, lcsh:R, Biology and Life Sciences, Signaling cascades, Computational Biology, Calcinosis, Cell Differentiation, Arteries, Genomics, Femoral Arteries, Genome Analysis, Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Carotid Arteries, TGF-beta signaling cascade, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cardiovascular Anatomy, Blood Vessels, lcsh:Q, Anatomy, Cellular Types, Physiological Processes, Transcriptome, Transcriptome Analysis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

International audience; Vascular calcification is a strong and independent predictive factor for cardiovascular complications and mortality. Our previous work identified important discrepancies in plaque composition and calcification types between carotid and femoral arteries. The objective of this study is to further characterize and understand the heterogeneity in vascular calcifica-tion among vascular beds, and to identify molecular mechanisms underlying this process. We established ECLAGEN biocollection that encompasses human atherosclerotic lesions and healthy arteries from different locations (abdominal, thoracic aorta, carotid, femoral, and infrapopliteal arteries) for histological, cell isolation, and transcriptomic analysis. Our results show that lesion composition differs between these locations. Femoral arteries are the most calcified arteries overall. They develop denser calcifications (sheet-like, nodule), and are highly susceptible to osteoid metaplasia. These discrepancies may derive from intrinsic differences between SMCs originating from these locations, as microarray analysis showed specific transcriptomic profiles between primary SMCs isolated from each arterial bed. These molecular differences translated into functional disparities. SMC from femoral arteries showed the highest propensity to mineralize due to an increase in basal TGFβ sig-naling. Our results suggest that biological heterogeneity of resident vascular cells between arterial beds, reflected by our transcriptomic analysis, is critical in understanding plaque biology and calcification, and may have strong implications in vascular therapeutic approaches.

Published
2018
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15. IMSYC IMmunologic SYnovitis sCore: A New Score for Synovial Membrane Characterization In Inflammatory And Non-Inflammatory Arthritis

Author

S Touchais, T Garraud, Benoit Le Goff, Noura Biha, Vincent Crenn, Jérôme Amiaud, Guillaume Venet, Aurélie Najm, Veit Krenn, Frédéric Blanchard, Céline Charrier, maurice, sandrine, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Département de Chirurgie Orthopédique [CHD de la Roche-sur-Yon], Centre Hospitalier Départemental site de la Roche-sur-Yon (CHD de la Roche-sur-Yon), Clinique chirurgicale orthopédique et traumatique [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Medical care centre [Trier, Germany] (MVZ), Zentrum für Histologie, Zytologie und Molekulare Diagnostik [Trier, Germany], This work was supported by Inserm, the Arthritis Foundation, Pfizer and the Région Pays de la Loire (Bioregate)., and Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon

Subjects
Male, medicine.medical_specialty, Inflammatory arthritis, Arthritis, Osteoarthritis, Gastroenterology, Severity of Illness Index, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Synovectomy, Synovitis, Internal medicine, medicine, Humans, 030212 general & internal medicine, Rheumatoid arthritis, 030203 arthritis & rheumatology, Inflammation, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Synovial Membrane, Biomarker, Middle Aged, medicine.disease, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Biomarker (medicine), Female, Synovial membrane, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; OBJECTIVES:Krenn synovitis Score has been developed by Krenn et al. in order to assess synovitis severity and is used in synovial research. Cell signature of synovial tissue can be studied using immunohistochemistry and is of interest as a biomarker for both prognosis and prediction of response to treatment. However, no synovitis score including immunohistochemistry exists yet. In order to answer this unmet need, we propose a new Immunologic SYnovitis sCore (IMSYC) adding 5 components to the Krenn score: CD68, CD3, CD20, CD31 and Ki67 immunostaining. In this study, we aimed to validate this new IMSYC by studying its diagnostic performances in a well-defined collection of synovial samples.METHODS:Synovial samples from patients were obtained during surgical procedures. CD68, CD3, CD20, CD31 and KI67 immunohistochemistry were performed.RESULTS:77 patients were included. 45 were females, mean age was 63.1 years. 40 had inflammatory arthritis, mainly rheumatoid arthritis (31/40). Non inflammatory arthritis group included 35 patients with mainly osteoarthritis. Mean Krenn score and IMSYC were significantly higher in the inflammatory group (p

Published
2018
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16. The enigmatic role of IL-38 in inflammatory diseases

Author

Mathilde Harel, T Garraud, Marie-Astrid Boutet, Frédéric Blanchard, Benoit Le Goff, maurice, sandrine, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Rhumatologie (Rhumato - HD - NANTES), Hôtel-Dieu de Nantes, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by Inserm, the Arthritis Foundation, the French Society of Rheumatology, Pfizer and the Région Pays de la Loire (Bioregate)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
0301 basic medicine, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Immunology, Arthritis, Inflammation, Context (language use), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Psoriatic arthritis, Mice, Psoriasis, medicine, Immunology and Allergy, Animals, Humans, Spondylitis, Ankylosing, Receptors, Cytokine, Receptor, IL-1F, Ankylosing spondylitis, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Interleukins, Arthritis, Psoriatic, Toll-Like Receptors, Receptors, Interleukin-1, Cell Differentiation, Receptors, Interleukin, medicine.disease, 3. Good health, IL-38, 030104 developmental biology, Cytokine, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Th17 Cells, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Interleukin-1
Abstract

International audience; IL-38 is the most recently discovered cytokine of the IL-1 family and is considered a potential inhibitor of the IL-1 and Toll-like receptor families. IL-38 exerts anti-inflammatory properties, especially on macrophages, by inhibiting secretion of pro-inflammatory cytokines, leading to reduced T-lymphocyte TH17 maturation. IL-38 has been studied most extensively in the context of chronic inflammatory diseases, particularly arthritis, where it is considered an attractive new drug candidate. IL-38 research has entered a new phase, with the realization that IL-38 is important in the pathophysiology of TH17 dependent-diseases (psoriasis, psoriatic arthritis and anky-losing spondylitis). In this review, we provide a critical evaluation of several controversial issues concerning IL-38 function and regulation. There is effectively contrasting data regarding IL-38: it is produced in conditions such as apoptosis, necrosis or inflammation, but data is lacking regarding IL-38 processing and biological function. Furthermore, the receptor for IL-38 has yet to be identified, although three candidate receptors – IL-1R1, IL-36R and IL-1RAPL1–have been proposed. Future studies will hopefully uncover new aspects of this enigmatic cytokine.

Published
2017
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17. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study

Author

Cécile Verite-Goulard, Nadir Cheurfa, Laurence Brugières, Sophie Piperno-Neumann, Laure Saumet, Nathalie Gaspar, Nadège Corradini, Perrine Marec-Berard, Hervé Brisse, Marie-Cécile Le Deley, Françoise Rédini, Claudine Schmitt, Gsf-Geto (Groupe Sarcome Français), Jessy Delaye, Hélène Pacquement, Emmanuelle Bompas, Marie-Pierre Castex, Jean-Claude Gentet, Bob-Valéry Occean, Natacha Entz-Werle, Cyril Lervat, Eric Mascard, Marie-Dominique Tabone, Corine Bouvier, Sfce, Antoine Italiano, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département d'oncologie pédiatrique [Institut Curie, Paris], Institut Curie [Paris], Département d'oncologie médicale [Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Département de pathologie [CHU La Timone, Marseille], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de l'Imagerie [Institut Curie, Paris], Paris-Sciences-et-Lettres Research University [Paris], Département d'oncologie pédiatrique [CHU Toulouse], CHU Toulouse [Toulouse], Département d'Oncologie Pédiatrique [CHU Nantes], Hôpital Mère-Enfant, CHU de Nantes, UNICANCER [Paris], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département d'Oncologie Pédiatrique [CHU Hautepierre, Strasbourg], Hôpital de Hautepierre [Strasbourg], Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département d'oncologie médicale, Institut Bergonié [Bordeaux], Unité d'oncologie pédiatrique [Centre Oscar Lambret, Lille], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Département d'oncologie pédiatrique [Centre Léon Bérard, Lyon], Centre Léon Bérard [Lyon], Service de chirurgie orthopédique et traumatologie pédiatrique [CHU Necker ], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département d'oncologie pédiatrique [Hôpital A. de Villeneuve, Montpellier], Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département d'oncologie pédiatrique [CHU Bordeaux], Hôpital des Enfants - Groupe hospitalier Pellegrin - CHU de Bordeaux, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Lille Nord de France (COMUE)-UNICANCER, Département d'Oncologie Médicale [Institut Curie, Paris], French National Cancer Institute (INCa) (INCA RC004 and PHRC-K13-041), NOVARTIS, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l’Enfant., the SFCE (Société Française des Cancers de l’Enfant et l’adolescent), GSF-GETO (Groupe Sarcome Français), the UNICANCER sarcoma group., Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université de Lille-UNICANCER, and maurice, sandrine

Subjects
Male, 0301 basic medicine, Cancer Research, medicine.medical_treatment, Kaplan-Meier Estimate, Zoledronic Acid, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Young adult, Child, Etoposide, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Osteosarcoma, Ifosfamide, Diphosphonates, Imidazoles, Combined Modality Therapy, 3. Good health, Oncology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Child, Preschool, 030220 oncology & carcinogenesis, Female, France, medicine.drug, Adult, medicine.medical_specialty, Neutropenia, Adolescent, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Young Adult, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Chemotherapy, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, medicine.disease, Surgery, Regimen, 030104 developmental biology, Methotrexate, Doxorubicin, Cisplatin, business
Abstract

Background In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014. Methods Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate. Results 409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%). Conclusion M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.

Published
2017
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18. Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial

Author

Nicola Baldini, Elena Veronesi, Nathalie Chevallier, Enrique Gómez-Barrena, Philippe Rosset, Pierre Layrolle, Philippe Hernigou, Cristina Avendaño-Solá, Gabriela Ciapetti, Sandrine Fleury, Massimo Dominici, Tiziana Montemurro, Rosaria Giordano, José Cordero-Ampuero, Jose Rafael Cabrera, M.N. Fernández, Hélène Rouard, Juan Carlos Rubio-Suárez, Ramin Lotfi, Markus Rojewski, Christian Ehrnthaller, Luc Sensebé, Hubert Schrezenmeier, Markus Huber-Lang, Florian Gebhard, Charles Henri Flouzat-Lachaniette, Norma G. Padilla-Eguiluz, Julien Stanovici, Davide Maria Donati, Carmen Panaitescu, Rosa Gonzalo-Daganzo, Eduardo García-Rey, Servicio de Cirugía Ortopédica y Traumatología [Madrid, Spain], Universidad Autonoma de Madrid (UAM)-Hospital Universitario La Paz-IdiPAZ and Facultad de Medicina [Madrid, Spain], Service de Chirurgie Orthopédique et Traumatologique 2 [CHU Tours], Hôpital Trousseau (Tours)-Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery [Ulm, Germany], Universität Ulm - Ulm University [Ulm, Allemagne]-Center of Surgery [Ulm, Germany], Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine [Bologna, Italy], University of Bologna-Department of Biomedical and Neuromotor Sciences [Bologna, Italy], Istituto Ortopedico Rizzoli [Bologna, Italy]-Istituto Ortopedico Rizzoli [Bologna, Italy], Etablissement Français du Sang Ile de France (EFS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Servicio de Hematología [Madrid, Spain], Universidad Autonoma de Madrid (UAM)-Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Cell Factory, Center for Cellular Therapy and Cryobiology [Milano, Italy], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Victor Babes University of Medicine and Pharmacy [Timisoara, Romania], Laboratory of Cellular Therapies [Modena, Italy], University - Hospital of Modena and Reggio Emilia [Modena, Italy]- Department of Medical and Surgical Sciences for Children & Adults [Modena, Italy], Institute for Clinical Transfusion Medicine and Immunogenetic Ulm [Ulm, Germany], Institut für Klinische Transfusionsmedizin und Immungenetik Ulm -IKT [Ulm, Germany], Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876)., Hospital Universitario La Paz-IdiPAZ and Facultad de Medicina [Madrid, Spain]-Universidad Autonoma de Madrid (UAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Université Francois Rabelais [Tours]-Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Victor Babeş University of Medicine and Pharmacy (UMFT), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), UAM. Departamento de Cirugía, UAM. Departamento de Farmacología, UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université Francois Rabelais [Tours]-Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Gómez-Barrena, Enrique, Rosset, Philippe, Gebhard, Florian, Hernigou, Philippe, Baldini, Nicola, Rouard, Helène, Sensebé, Luc, Gonzalo-Daganzo, Rosa M., Giordano, Rosaria, Padilla-Eguiluz, Norma, García-Rey, Eduardo, Cordero-Ampuero, José, Rubio-Suárez, Juan Carlo, Stanovici, Julien, Ehrnthaller, Christian, Huber-Lang, Marku, Flouzat-Lachaniette, Charles Henri, Chevallier, Nathalie, Donati, Davide Maria, Ciapetti, Gabriela, Fleury, Sandrine, Fernandez, Manuel-Nicolá, Cabrera, José-Rafael, Avendaño-Solá, Cristina, Montemurro, Tiziana, Panaitescu, Carmen, Veronesi, Elena, Rojewski, Markus Thoma, Lotfi, Ramin, Dominici, Massimo, Schrezenmeier, Hubert, Layrolle, Pierre, Universidad Autónoma de Madrid (UAM)-Hospital Universitario La Paz-IdiPAZ and Facultad de Medicina [Madrid, Spain], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université Francois Rabelais [Tours], University of Bologna/Università di Bologna-Department of Biomedical and Neuromotor Sciences [Bologna, Italy], Universidad Autónoma de Madrid (UAM)-Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and maurice, sandrine

Subjects
Calcium Phosphates, Biocompatible Materials, 02 engineering and technology, Bone tissue engineering, Fractures, Bone, Femur, media_common, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, 021001 nanoscience & nanotechnology, 3. Good health, Clinical trial, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Mechanics of Materials, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, medicine.medical_specialty, Bioceramic, Medicina, Biophysics, Ceramics and Composite, Bioengineering, Mesenchymal Stem Cell Transplantation, Non-union, Transplantation, Autologous, Non union, Expanded autologous BM-hMSC, Biomaterials, 03 medical and health sciences, medicine, media_common.cataloged_instance, Humans, Humerus, Tibia, European union, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, 030304 developmental biology, Cell Proliferation, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Mesenchymal stem cell, Mesenchymal Stem Cells, ATMP, Biomaterial, Surgery, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, Biophysic, Fractures, Ununited, Ceramics and Composites, Feasibility Studies, Bone marrow, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. Methods: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5–10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. Findings: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). Interpretation: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. Funding: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876)., The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/FP7-HEALTH-2009); REBORNE Project (GA: 241876)

Published
2017
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19. Calcific tendonitis of the rotator cuff: From formation to resorption

Author

Frédéric Blanchard, Christelle Darrieutort-Laffite, Benoit Le Goff, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Rhumatologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), and maurice, sandrine

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Shoulder, Tendonitis, Tendons, 03 medical and health sciences, Rotator Cuff, 0302 clinical medicine, Rheumatology, Apatites, medicine, Humans, Rotator cuff, Osteopontin, Apatite, 030203 arthritis & rheumatology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, biology, business.industry, Shoulder Joint, Calcinosis, medicine.disease, 3. Good health, Tendon, Resorption, 030104 developmental biology, medicine.anatomical_structure, Calcific tendonitis, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Tendinopathy, biology.protein, Fibrocartilage, Subacromial bursa, business, Calcification
Abstract

International audience; Calcific tendonitis of the rotator cuff is due to apatite deposits in the shoulder tendons. Patients affected by calcific tendonitis have chronic shoulder pain and disability. Although the disease is frequent, about 10 to 42% of painful shoulders, mechanisms leading to this pathological mineralization are still largely unknown. Research reported in the 90s suggested that the formation of calcific deposits is linked to cells looking like chondrocytes identified around calcium deposits within a fibrocartilage area. They were considered to be derived from tenocytes but more recently, tendon stem cells, able to differentiate into chondrocytes, were isolated. The pro-mineralizing properties of these chondrocytes-like cells, especially the role of alkaline phosphatase, are not currently clarified. The calcium deposits contain poorly crystalline carbonated apatite associated with protein. Among these proteins, only osteopontin has been consistently identified as a potential regulating factor. During the disease, spontaneous resorption can occur with migration of apatite crystals into the subacromial bursa causing severe pain and restriction of movement. In in vivo and in vitro experiments, apatite crystals were able to induce an influx of leucocytes and a release of IL-1β and IL-18 through the activation of the NLRP3 inflammasome. However, mechanisms leading to spontaneous resolution of this inflammation and disappearance of the calcification still need to be elucidated.

Published
2017
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20. Connexin43 intercellular communication drives the early differentiation of human bone marrow stromal cells into osteoblasts

Author

Julie Talbot, Dominique Heymann, Mathilde Mullard, Franck Verrecchia, Régis Brion, Sarah Morice, Audrey Lamora, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], maurice, sandrine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
0301 basic medicine, Small interfering RNA, Stromal cell, Time Factors, Physiology, Cellular differentiation, Clinical Biochemistry, Bone Marrow Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, Biology, Transfection, Connexins, gap junction, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Osteogenesis, medicine, Humans, Transcription factor, Cells, Cultured, Osteoblasts, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Gap junction, Gap Junctions, Osteoblast, Cell Biology, In vitro, Cell biology, human bone marrow stromal cells, connexin43, RUNX2, cell differentiation, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Connexin 43, Immunology, cardiovascular system, intercellular communication, osteoblast, Glycyrrhetinic Acid, RNA Interference, Stromal Cells, Oligopeptides, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract

International audience; Although it has been demonstrated that human bone marrow stromal cells (hBMSCs) express the ubiquitous connexin43 (Cx43) and form functional gap junctions, their role in the early differentiation of hBMSCs into osteoblasts remains poorly documented. Using in vitro assays, we show that Cx43 expression and gap junctional intercellular communication (GJIC) are increased during the differentiation of hBMSCs into osteoblasts, both at the protein and mRNA levels. Two independent procedures to reduce GJIC, a pharmacological approach with GJIC inhibitors (18α-glycyrrhetinic acid and Gap27 peptide) and a molecular approach using small interfering RNA against Cx43, demonstrated that the presence of Cx43 and functional junctional channels are essential to the ability of hBMSCs to differentiate into osteoblasts in vitro. In addition, a reduced GJIC decreases the expression of Runx2, the major transcription factor implicated in the control of osteoblast commitment and early differentiation of hBMSCs into osteoblasts, suggesting that GJIC mediated by Cx43 is implicated in this process. Together our results demonstrate that GJIC mediated by the Cx43 channels plays a central role throughout the differentiation of hBMSC into osteoblasts, from the early stages to the process of mineralization. K E Y W O R D S cell differentiation, connexin43, gap junction, human bone marrow stromal cells, intercellular communication, osteoblast

Published
2017
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21. Interaction of Cutibacterium ( formerly Propionibacterium) acnes with bone cells: a step toward understanding bone and joint infection development

Author

Dominique Heymann, Guillaume Ghislain Aubin, Didier Lepelletier, Cédric Jacqueline, Jean-Philippe Lavigne, Régis Brion, Marc Baud'huin, Stéphane Corvec, Karim Asehnoune, François Gouin, Service de bactériologie et hygiène hospitalière [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Virulence bactérienne et maladies infectieuses (VBMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de Microbiologie [Nîmes], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Clinique chirurgicale orthopédique et traumatique [Nantes], Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Thérapeutiques Cliniques et Expérimentales des Infections, Université de Nantes ( UN ), Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Virulence bactérienne et maladies infectieuses, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), European Associated Laboratory [Sheffield, UK] ( Sarcoma Research Unit ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), maurice, sandrine, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0301 basic medicine, Cell Survival, 030106 microbiology, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Genome, Article, Monocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Microbiology, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, Propionibacterium acnes, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cell Line, Tumor, Bone cell, Humans, Gene, Pathogen, Gram-Positive Bacterial Infections, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Whole Genome Sequencing, biology, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology.organism_classification, Phenotype, 3. Good health, Resorption, 030104 developmental biology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Multilocus sequence typing, Bone Diseases, Joint Diseases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Multilocus Sequence Typing
Abstract

Cutibacterium acnes (formerly Propionibacterium acnes) is recognized as a pathogen in foreign-body infections (arthroplasty or spinal instrumentation). To date, the direct impact of C. acnes on bone cells has never been explored. The clade of 11 C. acnes clinical isolates was determined by MLST. Human osteoblasts and osteoclasts were infected by live C. acnes. The whole genome sequence of six isolates of this collection was analyzed. CC36 C. acnes strains were significantly less internalized by osteoblasts and osteoclasts than CC18 and CC28 C. acnes strains (p ≤ 0.05). The CC18 C. acnes ATCC6919 isolate could survive intracellularly for at least 96 hours. C. acnes significantly decreased the resorption ability of osteoclasts with a major impact by the CC36 strain (p ≤ 0.05). Genome analysis revealed 27 genes possibly linked to these phenotypic behaviors. We showed a direct impact of C. acnes on bone cells, providing new explanations about the development of C. acnes foreign-body infections.

Published
2017
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22. Response to: ‘Does IL-38 act on macrophages and/or dendritic cells in arthritis?’ by Jiang et al

Author

Benoit Le Goff, Marie-Astrid Boutet, Frédéric Blanchard, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes), and maurice, sandrine

Subjects
0301 basic medicine, Experimental arthritis, Immunology, Anti-Inflammatory Agents, Arthritis, Inflammation, Infections, General Biochemistry, Genetics and Molecular Biology, Proinflammatory cytokine, Disease activity, Mice, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, medicine, Animals, Humans, Immunology and Allergy, education, Disease Activity, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Interleukins, Macrophages, Dendritic Cells, medicine.disease, 3. Good health, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cancer research, Allograft inflammatory factor 1, Immunohistochemistry, medicine.symptom, business, Adaptor molecule, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

We appreciate the comments by Jiang et al 1 on our study showing that IL-38 overexpression has anti-inflammatory effects in experimental arthritis presumably through decreased production of proinflammatory cytokines by macrophages.2 Jiang et al point out that the Iba1 marker used in our immunohistochemistry analysis is also expressed by dendritic cells (DCs) and that IL-23, whose expression is reduced by IL-38, is also highly expressed by DCs. Therefore, IL-38 could target DCs in addition to macrophages. Ionised calcium-binding adaptor molecule 1 (Iba1) also known as allograft inflammatory factor 1 (AIF-1) is widely accepted as a pan-macrophage marker expressed in …

Published
2017
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23. Involvement of sphingosine kinase/sphingosine 1-phosphate metabolic pathway in spondyloarthritis

Author

Benoit Le Goff, Leyre Brizuela, Anne Briolay, T Garraud, David Magne, Marie-Astrid Boutet, Alaeddine El Jamal, Frédéric Blanchard, Carole Bougault, Saida Mebarek, maurice, sandrine, Métabolisme, Enzymes et Mécanismes Moléculaires (MEM²), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), This work was supported by grant from 'Société Française de Rhumatologie (SFR)' [2818, 2014–2015]., Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL)

Subjects
0301 basic medicine, Adult, Male, Histology, Mineralization, Adolescent, Physiology, Endocrinology, Diabetes and Metabolism, Sphingosine kinase, Biology, Chondrocyte, 03 medical and health sciences, chemistry.chemical_compound, Mice, Young Adult, Calcification, Physiologic, Sphingosine, Spondylarthritis, Spondyloarthritis, medicine, Animals, Humans, Sphingosine-1-phosphate, Aged, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Kinase, Osteoblast, Cell cycle, Middle Aged, 3. Good health, Phosphotransferases (Alcohol Group Acceptor), 030104 developmental biology, medicine.anatomical_structure, chemistry, Sphingosine 1-phosphate, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Immunology, Cancer research, Alkaline phosphatase, Female, Lysophospholipids
Abstract

International audience; Spondyloarthritis (SpA) is a relatively common chronic inflammatory joint disorder, with a prevalence of about 0.2–0.5% worldwide. The primary target of the pathological process is the enthesis, where tendons and ligaments attach to underlying bone. These insertion sites are hotspots of bone formation (enthesophytes), which can lead to ankylosis. Unfortunately, the mechanisms causing the onset and progression of entheseal ossification remain largely unknown. Sphingosine 1-phosphate (S1P), a lipid generated after sphingosine phosphorylation by sphin-gosine kinases 1 and 2 (SK1/2), plays important roles in cell proliferation, differentiation and survival. S1P regulates fundamental biological processes such as cell cycle, inflammatory response or bone homeostasis. Indeed, S1P has been involved in some of most-spread skeletal diseases such as rheumatoid arthritis or osteoarthritis. On the other hand, the implication of S1P in SpA has not been explored yet. In the present work, we observed by ELISA that S1P content was significantly increased in the serum of SpA patients (6.1 ± 4.2 μM, n = 21) compared to healthy donors (1.6 ± 0.9 μM, n = 12). In vitro, gene expression of SK1 and SK2 as well as their activity were increased during differentiation of primary murine chondrocytes and osteoblasts into mineralizing cells. In addition, mRNA of the S1P-specific transporter Spns2 and S1P secretion were augmented. Using the pharmacological drugs SKi (SK pan-inhibitor), PF-543 (SK1 specific inhibitor) or K-145 (SK2 specific inhibitor), we showed that the inhibition of SK1 and/or SK2 decreased matrix mineralization, alkaline phosphatase activity and the mRNA expression of Runx2 and Bglap in chondrocytes and osteoblasts. To our knowledge, this is the first study indicating that S1P levels are significantly increased in serum from SpA patients. Moreover, we showed in vitro that SK activity was involved in the mineralization capacity of osteoblasts and chondrocytes. S1P metabolic pathway may represent an ingenious therapeutic target for SpA in the future.

Published
2017
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24. Damage to inner ear structure during cochlear implantation: Correlation between insertion force and radio-histological findings in temporal bone specimens

Author

Daniele Bernardeschi, Olivier Sterkers, Daniele De Seta, Evelyne Ferrary, Renato Torres, Dominique Heymann, Guillaume Kazmitcheff, Yann Nguyen, Francesca Yoshie Russo, Jérôme Amiaud, maurice, sandrine, Réhabilitation Chirurgicale mini-Invasive et Robotisée de l'Audition, Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Sense Organs [Rome, Italy], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Optimisation et commande (OC), Unité de Mathématiques Appliquées (UMA), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris), Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Time Factors, Materials science, Inner ear trauma, medicine.medical_treatment, Translocation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Prosthesis Design, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cochlear implant, Temporal bone, Cadaver, Pressure, medicine, Humans, 030223 otorhinolaryngology, Cochlear implantation, Insertion force, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cochlea, Rupture, Analysis of Variance, Round window, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Temporal Bone, Anatomy, Cone-Beam Computed Tomography, Basilar membrane, Cochlear Implantation, Sensory Systems, Cochlear Implants, basilar membrane, cochlear implant, inner ear trauma, insertion force, scala tympani, translocation, medicine.anatomical_structure, Scala tympani, Ear, Inner, Microscopy, Electron, Scanning, Stress, Mechanical, Implant, Cadaveric spasm, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Cochlear implant insertion should be as least traumatic as possible in order to reduce trauma to the cochlear sensory structures. The force applied to the cochlea during array insertion should be controlled to limit insertion-related damage. The relationship between insertion force and histological traumatism remains to be demonstrated. Twelve freshly frozen cadaveric temporal bones were implanted with a long straight electrodes array through an anterior extended round window insertion using a motorized insertion tool with real-time measurement of the insertion force. Anatomical parameters, measured on a pre-implantation cone beam CT scan, position of the array and force metrics were correlated with post-implantation scanning electron microscopy images and histological damage assessment. An atraumatic insertion occurred in six cochleae, a translocation in five cochleae and a basilar membrane rupture in one cochlea. The translocation always occurred in the 150-to 180-degree region. In the case of traumatic insertion, different force profiles were observed with a more irregular curve arising from the presence of an early peak force (30 ± 18.2 mN). This corresponded approximately to the first point of contact of the array with the lateral wall of the cochlea. Atraumatic and traumatic insertions had significantly different force values at the same depth of insertion (p < 0.001, two-way ANOVA), and significantly different regression lines (y ¼ 1.34x þ 0.7 for atraumatic and y ¼ 3.37x þ 0.84 for traumatic insertion, p < 0.001, ANCOVA). In the present study, the insertion force was correlated with the intracochlear trauma. The 150-to 180-degree region represented the area at risk for scalar translocation for this straight electrodes array. Insertion force curves with different sets of values were identified for traumatic and atraumatic insertions; these values should be considered during motorized insertion of an implant so as to be able to modify the insertion parameters (e.g axis of insertion) and facilitate preservation of endocochlear structures.

Published
2017
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25. TRAIL delivered by mesenchymal stromal/stem cells counteracts tumor development in orthotopic Ewing sarcoma models

Author

Guiho, R., Biteau, K., Grisendi, G., Taurelle, J., Chatelais, M., Gantier, M., Heymann, D., Dominici, M., Redini, F., Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe labellisée Ligue contre le Cancer, Department of Medical and Surgical Sciences for Children and Adults [Modena, Italy] (Laboratory of Cellular Therapy), Università degli Studi di Modena e Reggio Emilia (UNIMORE), maurice, sandrine, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE)

Subjects
Gene Expression, Apoptosis, TRAIL, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, TNF-Related Apoptosis-Inducing Ligand, resistance, Mice, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genes, Reporter, Transduction, Genetic, Cell Line, Tumor, Animals, Humans, Ewing sarcoma, microenvironment, MSC, Medicine (all), Oncology, Cancer Research, Cell Proliferation, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Mesenchymal Stem Cells, mesenchymal stromal/stem cells (MSC), Disease Models, Animal, Cell Transformation, Neoplastic, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Caspases, Heterografts, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Ewing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL-induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full-length human TRAIL were co-cultured with several human EWS cell lines, inducing apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. In vivo, TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell-based delivery of a potent apoptosis-inducing factor could be relevant in EWS. Ewing sarcoma (EWS), the second most common malignant bone tumor in pediatric patients after osteosarcoma, is a rare form of cancer. It is highly metastatic and causes serious disruption to bone remodeling. EWS is identified by a chromo-somal translocation between the EWS gene on chromosome 22 and a member of the ETS transcription factor family, more often FLI1 on chromosome 11, leading to production of a fusion protein which behaves like an aberrant transcription factor. 1 The resulting fusion protein, EWS-FLI1, directly or indirectly modulates the expression of many genes, altering several cell functions such as cell cycle (by targeting p21/CDKN1A, Cyclin D and E, p57/KIP2, TGFa-, IGF-, or MAPK signaling pathways) or apoptosis (by targeting capase3 and members of the TNFa, IGF-1 and TGFb signaling pathways). 2 Transformed EWS cells appear as small, round and undifferentiated, and they are involved in major disruption of bone structure, with severe osteolytic lesions. The current therapeutic approach consists of surgery, neoad-juvant and adjuvant chemotherapy, and in some cases radiother-apy. The 5-year survival rate has barely changed in the past 30 years, and remains at around 70% for localized forms. 3 However, the rate falls drastically to around 20% for groups of metastatic patients or poor responders to chemotherapy. New avenues of research have been opened by using TNF-Related Apoptosis Inducing Ligand (TRAIL), a pro-apoptotic cytokine from the TNF superfamily. TRAIL can bind to five receptors: two death receptors—TRAIL-R1 (Death Receptor 4: DR4) and TRAIL-R2 (DR5)—two decoy receptors that do not transmit the death signal but that can confer resistance toward TRAIL-induced apoptosis-TRAIL-R3 (Decoy Receptor 1: DcR1) and TRAIL-R4 (DcR2)—and the soluble osteoprotegerin (OPG). TRAIL, by binding to DR4 and DR5, is able to induce apoptosis of tumor cells by activating the recruitment and cleavage of pro-caspase

Published
2016
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26. Exercise-Induced Vasculitis: A Review with Illustrated Cases

Author

Brigitte Dréno, Yann Le Bouch, Quentin Didier, Marc-Antoine Pistorius, Olivier Espitia, Thibaut Quillard, E. Cassagnau, Christelle Nicol, Bernard Planchon, Département de Médecine Interne [CHU Nantes], Hôtel-Dieu de Nantes-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), No funding was received for the preparation of this review., maurice, sandrine, and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)

Subjects
Male, medicine.medical_specialty, Hot Temperature, Biopsy, Histamine Antagonists, Dermatology, Venous stasis, Lesion, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Recurrence, medicine, Humans, Decompensation, Exercise, Glucocorticoids, Retrospective Studies, Skin, Burning Sensation, Leg, medicine.diagnostic_test, business.industry, 030229 sport sciences, General Medicine, Middle Aged, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Surgery, Treatment Outcome, Vasculitis, Leukocytoclastic, Cutaneous, Female, Histopathology, medicine.symptom, business, Vasculitis, Stockings, Compression, Body Temperature Regulation
Abstract

International audience; Although exercise-induced vasculitis (EIV) is usually misdiagnosed, it is not uncommon. Occurring mostly after prolonged exercise, especially in hot weather, EIV is an isolated cutaneous vasculitis with stereotypical presentation. This article reviews the clinical characteristics, treatments, and outcomes of EIV based on the published literature. We report 99 patients who developed EIV after walking, dancing, swimming, or hiking especially during hot weather, including the records of 16 patients with EIV treated at our hospital from 2007 to 2015. Erythematous or purpuric plaques arise on the lower legs, without the involvement of compression socks or stockings. Symptoms include itch, pain, and a burning sensation. EIV is an isolated cutaneous vasculitis. Lesions resolve spontaneously after 10 days. When triggering conditions persist, relapses are frequent (77.5 %). Histopathology demonstrates leukocytoclastic vasculitis in 95 % of cases with C3 or immunoglobulin M deposits in 88 and 46 % of cases, respectively. Blood investigations are negative. EIV appears to be a consequence of venous stasis induced by an acute failure of the muscle pump of the calf and thermoregulation decompensation. Both appear after prolonged and unusual exercise in hot weather. Treatment is not codified; topical corticosteroids may reduce symptoms and wearing light clothes might limit lesion occurrence.

Published
2016
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27. miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors

Author

Lidia Rodriguez Calleja, Benjamin Ory, Marc Baud'huin, Francois Lamoureux, Dominique Heymann, Camille Jacques, Thibaut Quillard, Equipe Labellisée LIGUE 2012 [Nantes], Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, p73, Antineoplastic Agents, Bone Neoplasms, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Sarcoma, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, microRNA, medicine, Humans, Cisplatin, Osteosarcoma, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, business.industry, chemoresistance, Tumor Protein p73, medicine.disease, 3. Good health, microRNAs, 030104 developmental biology, Primary bone, Oncology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer cell, Immunology, Cancer research, Sarcoma, Tumor Suppressor Protein p53, business, Research Paper, medicine.drug
Abstract

International audience; Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73β, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73β. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73β axis in the context of these malignancies.

Published
2016
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28. Evolution of serum cytokine profile after hematopoietic stem cell transplantation in systemic sclerosis patients

Author

Lucas C. M. Arruda, C Deligny, E I Grigore, J.M. van Laar, Fred P.H.T.M. Romijn, J. van Pelt, Z Marjanovic, Laurence Michel, Dominique Farge, Franck Verrecchia, N Levarht, Francette Jean-Louis, J Baraut, Raphaël Porcher, Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biostatistiques [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Klinische Chemie en Laboratoriumgeneeskunde - KCL [Leiden, Pays-Bas], Leiden University Medical Center (LUMC), Center for Cell-based Therapy [Ribeirão Preto, Brazil] (Regional Blood Center), University of São Paulo (USP)-Ribeirão Preto Medical School [Brazil], Department of Biochemistry and Immunology [Ribeirão Preto, Brazil], University of São Paulo (USP)- Ribeirã o Preto Medical School [Ribeirão Preto, Brazil], Department of rheumatology [Leiden, Pays-Bas], Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute of Cellular Medicine [Newcastle], Newcastle University [Newcastle], This work was supported by Groupe Francophone de Recherche sur la Sclérodermie (GFRS), Association des Sclérodermiques de France (ASF), INSERM, Agence Nationale pour la Recherche, the Délégation Régionale à la Recherche Clinique (DRRC) from the Assistance Publique-Hôpitaux de Paris (AP-HP), the French Ministry of Health (PHRC 1997 AOM 6597–030) and the Etablissement Français des Greffes., Universidade de São Paulo = University of São Paulo (USP)-Ribeirão Preto Medical School [Brazil], Universidade de São Paulo = University of São Paulo (USP)- Ribeirã o Preto Medical School [Ribeirão Preto, Brazil], Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and maurice, sandrine

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Pathology, T-Lymphocytes, medicine.medical_treatment, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematopoietic stem cell transplantation, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Fibrosis, Internal medicine, medicine, Journal Article, Humans, Progenitor cell, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Transplantation, Scleroderma, Systemic, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hematology, business.industry, Hematopoietic Stem Cell Transplantation, Middle Aged, medicine.disease, 3. Good health, Treatment Outcome, surgical procedures, operative, 030104 developmental biology, Graft-versus-host disease, Case-Control Studies, Immunology, Cytokines, Female, medicine.symptom, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Evolution of serum cytokine profile after hematopoietic stem cell transplantation in systemic sclerosis patients

Published
2016
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29. Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Author

Bénédicte Brounais-Le Royer, Séverine Battaglia, Franck Verrecchia, Françoise Rédini, Dominique Heymann, Francois Lamoureux, Thibaut Quillard, Benjamin Ory, Jérôme Amiaud, Marc Baud'huin, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe Labellisée LIGUE 2012 [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), This study was supported by l'Association pour la Recherche sur le Cancer (France), and Pfizer Global Research & Development (United States)., maurice, sandrine, and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)

Subjects
0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Apoptosis, Zoledronic Acid, Monocytes, Hsp90 inhibitor, Metastasis, Mice, 0302 clinical medicine, Neoplasm Metastasis, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Osteosarcoma, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Diphosphonates, Imidazoles, Drug Synergism, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Oncology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Disease Progression, Female, Signal Transduction, medicine.drug, Mice, Nude, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Osteoclast, Cell Line, Tumor, medicine, Animals, Humans, HSP90 Heat-Shock Proteins, Cell Proliferation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Cell growth, business.industry, Cancer, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Zoledronic acid, Immunology, Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Purpose: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma. Experimental Design: The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by Western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated bone lesions, and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14+ monocytes. Results: In osteosarcoma cell lines, PF4942847 inhibited cell growth in a dose-dependent manner (IC50 ±50 nmol/L) and induced apoptosis with an increase of sub-G1 fraction and cleaved PARP. These biologic events were accompanied by decreased expression of Akt, p-ERK, c-Met, and c-RAF1. When administered orally to mice bearing osteosarcoma tumors, PF4942847 significantly inhibited tumor growth by 80%, prolonged survival compared with controls, and inhibited pulmonary metastases by blocking c-Met, FAK, and MMP9 signaling. In contrast to 17-allylamino-17-demethoxygeldanamycin (17-AAG), PF4942847 did not induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions. Conclusions: All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma. Clin Cancer Res; 22(10); 2520–33. ©2015 AACR.

Published
2016
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30. Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Author

Jérôme Amiaud, Lidia Rodriguez Calleja, Marc Baud'huin, Benjamin Ory, Francois Lamoureux, James E. Bradner, Robert Owen, Thibaut Quillard, Martine Berreur, Camille Jacques, Gwendolen C. Reilly, Céline Charrier, Dominique Heymann, Bénédicte Brounais-LeRoyer, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Equipe Labellisée LIGUE 2012 [Nantes], Department of Materials Science and Engineering [Sheffield], University of Sheffield [Sheffield], Department of Medical Oncology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Dana-Farber Cancer Institute [Boston], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Camille Jacques is founded by INSERM (Institut National de la Santé et de la Recherche Médicale) and Région Pays de la Loire (grant no. 000381794)., ANR-16-CE14-0012,EPIBONE,Rôle des protéines à bromodomaines dans la physiologie osseuse normale(2016), European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), maurice, sandrine, and European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID

Subjects
0301 basic medicine, Physiology, Endocrinology, Diabetes and Metabolism, Cellular differentiation, Bromodomain, Osteoclasts, Cell Count, Epigenesis, Genetic, 0302 clinical medicine, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Osteoblast, Epigenetic, Nuclear Proteins, Cell Differentiation, Azepines, Organ Size, Cell biology, Chromatin, Biomechanical Phenomena, RUNX2, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Osteoclast, Female, Signal Transduction, musculoskeletal diseases, medicine.medical_specialty, BRD4, Histology, Inhibitor, Ovariectomy, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Transcription factor, Osteoblasts, Triazoles, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Osteoporosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Histone modifications are important for maintaining the transcription program. BET proteins, an important class of " histone reading proteins " , have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis.

Published
2016
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31. Cathepsin-Mediated Alterations in TGFß-Related Signaling Underlie Disrupted Cartilage and Bone Maturation Associated With Impaired Lysosomal Targeting

Author

Heather, Flanagan-Steet, Megan, Aarnio, Brian, Kwan, Pierre, Guihard, Aaron, Petrey, Mark, Haskins, Frederic, Blanchard, Richard, Steet, Complex Carbohydrate Research Center [Athens, GA, USA], University of Georgia [USA], Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Departments of Pathology and Clinical Studies [Philadelphia, PA, USA], University of Pennsylvania School of Veterinary Medicine, This work was supported by grants from NIGMS (GM-086524 and P40 OD101939) and the National ISMRD/MPS Society., maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Cathepsin K, Bone Morphogenetic Protein 2, Smad Proteins, Bone and Bones, Article, Chondrocytes, Mucolipidoses, Transforming Growth Factor beta, CARTILAGE, Animals, Humans, LYSOSOMAL, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Bone Development, Osteoblasts, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, ZEBRAFISH, CATHEPSINS, Cell Differentiation, SOX9 Transcription Factor, Zebrafish Proteins, TGFß, Phenotype, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cats, Collagen, Lysosomes, MLII, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract

International audience; Hypersecretion of acid hydrolases is a hallmark feature of mucolipidosis II (MLII), a lysosomal storage disease caused by loss of carbohydrate-dependent lysosomal targeting. Inappropriate extracellular action of these hydrolases is proposed to contribute to skeletal pathogenesis, but the mechanisms that connect hydrolase activity to the onset of disease phenotypes remain poorly understood. Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in MLII animals by demonstrating that it disrupts the balance of TGFß-related signaling during chondrogenesis. TGFß-like Smad2,3 signals are elevated and BMP-like Smad1,5,8 signals reduced in both feline and zebrafish MLII chondrocytes and osteoblasts, maintaining these cells in an immature state. Reducing either cathepsin K activity or expression of the transcriptional regulator Sox9a in MLII zebrafish significantly improved phenotypes. We further identify components of the large latent TGFß complex as novel targets of cathepsin K at neutral pH, providing a possible mechanism for enhanced Smad2,3 activation in vivo. These findings highlight the complexity of the skeletal disease associated with MLII and bring new insight to the role of secreted cathepsin proteases in cartilage development and growth factor regulation.

Published
2016
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32. Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease

Author

Franck Morel, Jérôme Amiaud, A. Bourreille, Marie-Astrid Boutet, Bénédicte Brulin, Céline Charrier, Maël Penhoat, M. Rolli‐Derkinderen, Frédéric Blanchard, B. Le Goff, Gaby Palmer, J.-C. Lecron, Géraldine Bart, Solenne Vigne, Cem Gabay, maurice, sandrine, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, Service Immunologie/Inflammation [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastroentérologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Division of Rheumatology [Geneva, Switzerland], Geneva University Hospital, Geneva-Department of Internal Medicine Specialties [Geneva, Switzerland], This work was supported by Inserm, the Arthritis Foundation and by a grant from the Swiss National Science Foundation (310030_135195 to CG). M.A.B. was a recipient of a fellowship from the French Ministry of Research., Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Genève (UNIGE), ROLLI-DERKINDEREN, MALVYNE, and Université de Genève = University of Geneva (UNIGE)

Subjects
0301 basic medicine, Keratinocytes, Male, rheumatoid arthritis, Arthritis, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Arthritis, Rheumatoid, Mice, Crohn Disease, Immunology and Allergy, Macrophage, Medicine, Intestinal Mucosa, Skin, ddc:616, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Imiquimod, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Synovial Membrane, Interleukin-36, Interleukin, psoriasis, 3. Good health, Crohn's disease, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Mice, Inbred DBA, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Rheumatoid arthritis, Aminoquinolines, medicine.symptom, Immunology, Plasma Cells, Inflammation, Enzyme-Linked Immunosorbent Assay, Cell Line, 03 medical and health sciences, Psoriasis, Animals, Humans, RNA, Messenger, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, business.industry, Interleukins, Macrophages, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Dendritic Cells, Original Articles, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, Arthritis, Experimental, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, CCL20, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, IL-36, Th17 Cells, Caco-2 Cells, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Interleukin-1
Abstract

Summary Interleukin (IL)-36α, IL-36β and IL-36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL-36Ra or IL-38, another potential IL-36 inhibitor, limit uncontrolled inflammation. The expression and role of IL-36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36β and IL-38 mRNA, was induced and correlated with IL-1β and T helper type 17 (Th17) cytokines (IL-17A, IL-22, IL-23, CCL20). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, β, γ, IL-36Ra and IL-38 were all elevated and correlated with IL-1β, CCL3, CCL4 and macrophage colony-stimulating factor (M-CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at relatively low levels and correlated with IL-1β and IL-17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL-36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68+ macrophages, dendritic/Langerhans cells and CD79α+ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL-36β and IL-36Ra were produced constitutively, but IL-36α, γ and IL-38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL-36 agonists/antagonists ratio.

Published
2016
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33. The second European interdisciplinary Ewing sarcoma research summit--A joint effort to deconstructing the multiple layers of a complex disease

Author

Nathan C. Sheffield, Andrei Zinovyev, Branka Radic Sarikas, Jeffrey A. Toretsky, Marc Ladanyi, Markus Metzler, Theodore Papamarkou, Guenther H. S. Richter, Enrique de Alava, Elizabeth S. Stewart, Patrick J. Grohar, Lee J. Helman, Beat W. Schäfer, Florencia Cidre-Aranaz, James F. Amatruda, Keri Schadler, Kimberly Stegmaier, Anang A. Shelat, Thomas G. P. Grunewald, Poul H. Sorensen, Paul S. Meltzer, Jaume Mora, Oscar M. Tirado, Takuro Nakamura, Joseph A. Ludwig, Olivier Delattre, Alejandro Sweet-Cordero, Uta Dirksen, Richard Moriggl, Peter J. Houghton, Claudia Rossig, Stephen L. Lessnick, Stefan Burdach, Karoly Szuhai, Elizabeth R. Lawlor, Kristiina Iljin, Franck Tirode, Wietske van der Ent, Françoise Rédini, Aykut Üren, Heinrich Kovar, Erika Brunet, Eberhard Korsching, Katia Scotlandi, Kalliopi Tsafou, Ewa Snaar-Jagalska, Unión Europea. Comisión Europea. 7 Programa Marco, Children’s Cancer Research Institute [Vienna, Austria], Department of Pediatrics [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Departments of Pediatrics, Molecular Biology and Internal Medicine [Dallas, TX, USA], University of Texas Southwestern Medical Center [Dallas], Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Children’s Cancer Research Center and Department of Pediatrics [Munich, Germany], Technical University and Comprehensive Cancer Center Munich - CCCM [Germany]-Klinikum rechts der Isar [Munich, Germany], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Laboratorio de Patología Molecular (USAL-CSIC), Centro de Investigación del Cáncer, Universitätsklinikum Münster [Munster, Germany], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Biology [Leiden, The Netherlands], Leiden University, Center for Cancer and Cell Biology [Grand Rapids, MI, USA], Van Andel Institute [Grand Rapids]-Helen DeVos Children’s Hospital [Grand Rapids, MI, USA], Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], Center for Cancer Rearch [Bethesda, MA, USA], National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Greehey Children’s Cancer Research Institute [San Antonio, TX, USA], The University of Texas Health Science Center at Houston (UTHealth), VTT Technical Research Centre of Finland (VTT), Institute of Bioinformatics [Muenster, Germany], University of Münster, Department of Pathology and Human Oncology and Pathogenesis Program [New York, NY, USA], Memorial Sloane Kettering Cancer Center [New York], Department of Pediatrics and Department of Pathology [Ann Arbor, MI, USA], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Division of Pediatric Hematology/ Oncology/BMT [Columbus, OH, USA], Abigail Wexner Research Institute, Nationwide Children's Hospital-Nationwide Children's Hospital, Department of Sarcoma Medical Oncology [Houston, TX, USA], The University of Texas M.D. Anderson Cancer Center [Houston], Genetics Branch [Bethesda, MD, USA] (Center for Cancer Research), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen [Germany], Department of Pediatric Oncology [Barcelona, Spain], Hospital Sant Joan de Déu [Barcelona], Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria], Institute of Animal Breeding and Genetics [Vienna, Austria] (Department for Biomedical Sciences), University of Veterinary Medicine [Vienna] (Vetmeduni), Division of Carcinogenesis [Tokyo, Japan], The Cancer Institute [Tokyo, Japan]-Japanese Foundation for Cancer Research [Tokyo, Japan], School of Mathematics and Statistics [Glasgow, UK], University of Glasgow, Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Pediatrics Research [Houston, TX, USA], Department of Oncology and Children’s Research Center [Zurich, Switzerland], University Children’s Hospital Zurich, CRS Development of Biomolecular Therapies [Bologna, Italy] (Experimental Oncology Lab), University of Bologna-The Rizzoli Institute [Bologna, Italy], Department of Chemical Biology and Therapeutics [Memphis,TN, USA], St Jude Children's Research Hospital, Department of Molecular Oncology [British Columbia, Canada], British Columbia Cancer Research Centre [British Columbia, Canada], Department of Pediatric Oncology [Boston, MA, USA], Dana-Farber Cancer Institute [Boston], Department of Developmental Neurobiology [Memphis, TN, USA], Division of Hematology and Oncology [Stanford, CA, USA] (Department of Pediatrics), Stanford University, Department of Molecular Cell Biology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Molecular Oncology Laboratory [Barcelona, Spain] (Sarcoma Research Group), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL)-L’Hospitalet de Llobregat [Barcelona, Spain], Department of Oncology [Washington, DC, USA], Georgetown University School of Medicine [Washington, DC USA], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), The conference was supported by the European Union’s Seventh Framework Programme grants 261743 (ENCCA) and 259348 (ASSET)., European Project: 259348,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,ASSET(2010), European Commission, Universiteit Leiden, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), University Hospital Erlangen = Uniklinikum Erlangen, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), University of Bologna/Università di Bologna-The Rizzoli Institute [Bologna, Italy], Universiteit Leiden-Universiteit Leiden, Mines Paris - PSL (École nationale supérieure des mines de Paris), maurice, sandrine, and ASSET: Analysing and Striking the Sensitivities of Embryonal Tumours - ASSET - - EC:FP7:HEALTH2010-11-01 - 2016-04-30 - 259348 - VALID

Subjects
0301 basic medicine, Oncogene Proteins, Fusion, Complex disease, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Neoplasms, Computational biology, Disease, Review, Sarcoma, Ewing, Biology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, medicine, Humans, development, geography, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, therapy, Summit, geography.geographical_feature_category, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, epigenetics, Proto-Oncogene Protein c-fli-1, ta1182, Gene rearrangement, medicine.disease, ta3122, microenvironment, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Susceptibility locus, Identification (biology), Sarcoma, RNA-Binding Protein EWS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Ewing sarcoma, Signal Transduction
Abstract

Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second >European interdisciplinary Ewing sarcoma research summit> assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNAsequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intratumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits., The conference was supported by the European Union’s Seventh Framework Programme grants 261743(ENCCA) and 259348 (ASSET).

Published
2016
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34. Pathogenic potential of Escherichia coli clinical strains from orthopedic implant infections towards human osteoblastic cells

Author

Bénédicte Brulin, Lise Crémet, Régis Brion, Karim Asehnoune, Nathalie Caroff, Stéphane Corvec, Cédric Jacqueline, Alexis Broquet, Dominique Heymann, Sandie Dauvergne, Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Département de bactériologie-hygiénique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Soins Intensifs [CHU Nantes] (Département d'anesthésie et de soins intensifs), This work was supported by the French 'Ministère de l’Enseignement Supérieur et de la Recherche'., maurice, sandrine, and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)

Subjects
medicine.disease_cause, Bacterial Adhesion, Hemolysin Proteins, Immunology and Allergy, human osteoblasts, Pathogen, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Microscopy, Confocal, Escherichia coli Proteins, alpha-hemolysin, Hemolysin, General Medicine, E coli, Endocytosis, 3. Good health, Infectious Diseases, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Staphylococcus aureus, Surgical Procedures, Operative, Pseudomonas aeruginosa, cytotoxicity, Gentamicin, Research Article, medicine.drug, Microbiology (medical), Prosthesis-Related Infections, Cell Survival, Population, Biology, Cell Line, Microbiology, Gentamicin protection assay, Escherichia coli, medicine, Humans, education, Osteoblasts, L-Lactate Dehydrogenase, General Immunology and Microbiology, Interleukin-6, Tumor Necrosis Factor-alpha, Gene Expression Profiling, Coculture Techniques, internalization, Orthopedics, TNF-α, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; One sentence summary: This study describes the interaction of Escherichia coli clinical strains with an osteoblastic cell line, showing no internalization unlike Staphylococcus aureus, but a strong cytotoxicity of the Hly-A producing strains. Editor: Patrik M. Bavoil ABSTRACT Escherichia coli is one of the first causes of Gram-negative orthopedic implant infections (OII), but little is known about the pathogenicity of this species in such infections that are increasing due to the ageing of the population. We report how this pathogen interacts with human osteoblastic MG-63 cells in vitro, by comparing 20 OII E. coli strains to two Staphylococcus aureus and two Pseudomonas aeruginosa strains. LDH release assay revealed that 6/20 (30%) OII E. coli induced MG-63 cell lysis whereas none of the four control strains was cytotoxic after 4 h of coculture. This high cytotoxicity was associated with hemolytic properties and linked to hlyA gene expression. We further showed by gentamicin protection assay and confocal microscopy that the non-cytotoxic E. coli were not able to invade MG-63 cells unlike S. aureus strains (internalization rate

Published
2015
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35. ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis

Author

Debashish Sahay, Leif W. Ellisen, Thibaut Quillard, Marc Baud'huin, Fernando Lecanda, Francois Lamoureux, Franck Verrecchia, Lidia Rodriguez Calleja, Dominique Heymann, Marta Tellez Gabriel, Céline Charrier, Régis Brion, Camille Jacques, Pierre Perrot, Jérôme Amiaud, Benjamin Ory, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Equipe Labellisée LIGUE 2012 [Nantes], Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Massachusetts General Hospital Cancer Center [Boston, MA, USA], Harvard Medical School [Boston] (HMS), C. Jacques was funded by INSERM and Region Pays de la loire, Philippe Hulin, Nantes University, PICell for time-lapsemicroscopy., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), maurice, sandrine, European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, Apoptosis, Metastasis, Immunoenzyme Techniques, Transactivation, Mice, Cell Movement, Transforming Growth Factor beta, Tumor Cells, Cultured, Protein Isoforms, Regulation of gene expression, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Osteosarcoma, Reverse Transcriptase Polymerase Chain Reaction, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Transcriptional Activation, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Neoplasms, Biology, Real-Time Polymerase Chain Reaction, Article, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, microRNA, medicine, Animals, Humans, RNA, Messenger, Psychological repression, Cell Proliferation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Wound Healing, Tumor Suppressor Proteins, Transforming growth factor beta, medicine.disease, Xenograft Model Antitumor Assays, Transplantation, MicroRNAs, 030104 developmental biology, Immunology, Cancer research, biology.protein, Gene Deletion, Transcription Factors
Abstract

Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ΔNp63α, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ΔNp63α-expressing cells within a TGFβ-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ΔNp63α-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ΔNp63α repressed miR-527 and miR-665, leading to the upregulation of two TGFβ effectors, SMAD4 and TβRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound-healing response. We show that ΔNp63α-mediated repression of miR-527/665 controls a TGFβ-dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236–51. ©2016 AACR.

Published
2015
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36. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion

Author

Haniel Alves Araújo, Thibaut Quillard, Peter Libby, Eugenia Shvartz, Galina K. Sukhova, Grégory Franck, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Division of Cardiovascular Medicine [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], This work was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL080472 to P.L.) and from the Donald W. Reynolds Foundation (to P.L.). H.A. was supported by the Fundacaopara o Amparo de Pesquisas do Estado de Sao Paulo, Brazil and the FundacaoLemann, Sao Paulo, Brazil. G.F. was supported by Harold M. English Fellowship Fund from the Harvard Medical School, and T.Q. received financial support from the Fondation Bettencourt Schueller and the Fondation pour la Recherche Me´dicale, Paris, France. A gift from James Annenburg La Vea provided support for parts of this work., maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Pathology, Neutrophils, Endothelial cells, Apoptosis, Muscle, Smooth, Vascular, Pathogenesis, Protein Phosphatase 1, TLR2, Hyaluronic Acid, RNA, Small Interfering, Hyaluronan, chemistry.chemical_classification, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cell adhesion molecule, Neutrophil, Fluoresceins, Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, Caspases, Cytokines, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Endothelium, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Stress, Physiological, medicine, Cell Adhesion, Humans, Acute Coronary Syndrome, Fluorescent Dyes, Reactive oxygen species, Rupture, Spontaneous, business.industry, Endoplasmic reticulum, Neutrophil extracellular traps, Toll-Like Receptor 2, NET, FASTTrack Basic Science, chemistry, Unfolded protein response, Leukocytes, Mononuclear, business, Leukocyte Elastase, Reactive Oxygen Species, Superficial erosion, Cell Adhesion Molecules, Biomarkers, Transcription Factor CHOP, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; AIMS:Superficial erosion of atheromata causes many acute coronary syndromes, but arises from unknown mechanisms. This study tested the hypothesis that Toll-like receptor-2 (TLR2) activation contributes to endothelial apoptosis and denudation and thus contributes to the pathogenesis of superficial erosion.METHODS AND RESULTS:Toll-like receptor-2 and neutrophils localized at sites of superficially eroded human plaques. In vitro, TLR2 ligands (including hyaluronan, a matrix macromolecule abundant in eroded lesions) induced endothelial stress, characterized by reactive oxygen species production, endoplasmic reticulum (ER) stress, and apoptosis. Co-incubation of neutrophils with endothelial cells (ECs) potentiated these effects and induced EC apoptosis and detachment. We then categorized human atherosclerotic plaques (n = 56) based on morphologic features associated with superficial erosion, 'stable' fibrotic, or 'vulnerable' lesions. Morphometric analyses of the human atheromata localized neutrophils and neutrophil extracellular traps (NETs) near clusters of apoptotic ECs in smooth muscle cell (SMC)-rich plaques. The number of luminal apoptotic ECs correlated with neutrophil accumulation, amount of NETs, and TLR2 staining in SMC-rich plaques, but not in 'vulnerable' atheromata.CONCLUSION:These in vitro observations and analyses of human plaques indicate that TLR2 stimulation followed by neutrophil participation may render smooth muscle cell-rich plaques susceptible to superficial erosion and thrombotic complications by inducing ER stress, apoptosis, and favouring detachment of EC.

Published
2015
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37. Controlled implant/soft tissue interaction by nanoscale surface modifications of 3D porous titanium implants

Author

Christian Debry, Nihal Engin Vrana, Pierre Layrolle, Marie-Hélène Metz-Boutigue, Philippe Lavalle, Laëtitia Salou, Agnès Dupret-Bories, Elisabeth Rieger, Biomatériaux et Bioingénierie (BB), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Faculté de chirurgie dentaire - Strasbourg, Université de Strasbourg (UNISTRA), Service Oto-Rhino-Laryngologie [HUS Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Biomedical Tissues SAS [Nantes], Protip Medical [Strasbourg], This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 606624 (NanoTi). This study has been partially funded by Protip Medical, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, France, and Ligue contre le cancer Alsace, France., European Project: 606624,EC:FP7:SME,FP7-SME-2013,NANOTI(2014), maurice, sandrine, Development of a titanium dental implant with superior antibacterial properties - NANOTI - - EC:FP7:SME2014-02-01 - 2016-01-31 - 606624 - VALID, Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Materials science, food.ingredient, Cell Survival, Surface Properties, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Nanotechnology, Microscopy, Atomic Force, Gelatin, Adsorption, food, Surface roughness, Animals, Humans, General Materials Science, Rats, Wistar, Cells, Cultured, Titanium, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Anodizing, technology, industry, and agriculture, Blood Proteins, Prostheses and Implants, equipment and supplies, Nanostructures, Rats, [SDV] Life Sciences [q-bio], chemistry, Self-healing hydrogels, Microscopy, Electron, Scanning, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Implant, Hydrophobic and Hydrophilic Interactions, Porosity, Biomedical engineering, Protein adsorption
Abstract

International audience; Porous titanium implants are widely employed in the orthopaedics field to ensure good bone fixation. Recently, the use of porous titanium implants has also been investigated in artificial larynx development in a clinical setting. Such uses necessitate a better understanding of the interaction of soft tissues with porous titanium structures. Moreover, surface treatments of titanium have been generally evaluated in planar structures, while the porous titanium implants have complex 3 dimensional (3D) architectures. In this study, the determining factors for soft tissue integration of 3D porous titanium implants were investigated as a function of surface treatments via quantification of the interaction of serum proteins and cells with single titanium microbeads (300–500 µm in diameter). Samples were either acid etched or nanostructured by anodization. When the samples are used in 3D configuration (porous titanium discs of 2 mm thickness) in vivo (in subcutis of rats for 2 weeks), a better integration was observed for both anodized and acid etched samples compared to the non-treated implants. If the implants were also pre-treated with rat serum before implantation, the integration was further facilitated. In order to understand the underlying reasons for this effect, human fibroblast cell culture tests under several conditions (directly on beads, beads in suspension, beads encapsulated in gelatin hydrogels) were conducted to mimic the different interactions of cells with Ti implants in vivo. Physical characterization showed that surface treatments increased hydrophilicity, protein adsorption and roughness. Surface treatments also resulted in improved adsorption of serum albumin which in turn facilitated the adsorption of other proteins such as apolipoprotein as quantified by protein sequencing. The cellular response to the beads showed considerable difference with respect to the cell culture configuration. When the titanium microbeads were entrapped in cell-laden gelatin hydrogels, significantly more cells migrated towards the acid etched beads. In conclusion, the nanoscale surface treatment of 3D porous titanium structures can modulate in vivo integration by the accumulative effect of the surface treatment on several physical factors such as protein adsorption, surface hydrophilicity and surface roughness. The improved protein adsorption capacity of the treated implants can be further exploited by a pre-treatment with autologous serum to render the implant surface more bioactive. Titanium microbeads are a good model system to observe these effects in a 3D microenvironment and provide a better representation of cellular responses in 3D.

Published
2015
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38. Bone Like Arterial Calcification in Femoral Atherosclerotic Lesions: Prevalence and Role of Osteoprotegerin and Pericytes

Author

Jean-Michel Davaine, Yann Gouëffic, Florian Guilbaud, Dominique Heymann, M.-F. Heymann, Mathias Chatelais, Régis Brion, Béatrice Guyomarch, Thibaut Quillard, Meadhbh Á. Brennan, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chirurgie Vasculaire [Centre Hospitalier René-Dubos], Centre Hospitalier René Dubos [Pontoise], Service de Chirurgie cardiaque et thoracique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Nantes - Nantes Atlantique Universités, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Medical Oncology [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], This work was funded by an Allocation Nationale de Recherche (ANR, ANR-11-BSV1-0036) for physiopathology and by an inter-regional Programme Hospitalier de Recherche Clinique (PHRC, API11/N/076)., Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Unité de recherche de l'institut du thorax (ITX-lab), and maurice, sandrine

Subjects
0301 basic medicine, Male, Pathology, 030204 cardiovascular system & hematology, 0302 clinical medicine, Vascular pericytes, Prevalence, Functional ability, 030212 general & internal medicine, Prospective Studies, Cells, Cultured, Medicine(all), [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Osteoblast, Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Femoral Artery, Arterial calcification, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, England, RANKL, Female, Pericyte, Cardiology and Cardiovascular Medicine, musculoskeletal diseases, medicine.medical_specialty, Endarterectomy, 03 medical and health sciences, Peripheral Arterial Disease, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Osteoprotegerin, Osteoclast, medicine, Humans, Vascular Calcification, Aged, Osteoid, business.industry, RANK Ligand, Atherosclerosis, 030104 developmental biology, biology.protein, Surgery, business, Pericytes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; OBJECTIVE/BACKGROUND:Arterial calcification, a process that mimics bone formation, is an independent risk factor of cardiovascular morbidity and mortality, and has a significant impact on surgical and endovascular procedures and outcomes. Research efforts have focused mainly on the coronary arteries, while data regarding the femoral territory remain scarce.METHODS:Femoral endarterectomy specimens, clinical data, and plasma from a cohort of patients were collected prospectively. Histological analysis was performed to characterize the cellular populations present in the atherosclerotic lesions, and that were potentially involved in the formation of bone like arterial calcification known as osteoid metaplasia (OM). Enzyme linked immunosorbent assays and cell culture assays were conducted in order to understand the cellular and molecular mechanisms underlying the formation of OM in the lesions.RESULTS:Twenty-eight of the 43 femoral plaques (65%) displayed OM. OM included osteoblast and osteoclast like cells, but very few of the latter exhibited the functional ability to resorb mineral tissue. As in bone, osteoprotegerin (OPG) was significantly associated with the presence of OM (p = .04). Likewise, a high plasma OPG/receptor activator for the nuclear factor kappa B ligand (RANKL) ratio was significantly associated with the presence of OM (p = .03). At the cellular level, there was a greater presence of pericytes in OM+ compared with OM- lesions (5.59 ± 1.09 vs. 2.42 ± 0.58, percentage of area staining [region of interest]; p = .04); in vitro, pericytes were able to inhibit the osteoblastic differentiation of human mesenchymal stem cells, suggesting that they are involved in regulating arterial calcification.CONCLUSION:These results suggest that bone like arterial calcification (OM) is highly prevalent at femoral level. Pericyte cells and the OPG/RANK/RANKL triad seem to be critical to the formation of this ectopic osteoid tissue and represent interesting potential therapeutic targets to reduce the clinical impact of arterial calcification.

Published
2015
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39. Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases

Author

Lamora, A., Mullard, M., Amiaud, J., Brion, R., Heymann, D., Redini, F., Verrecchia, F., maurice, sandrine, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Equipe labellisée Ligue contre le Cancer, Centre Hospitalier Universiatire Hôtel-Dieu de Nantes (CHU Hôtel-Dieu), INSERM Liliane Bettencourt School [Paris], INSERM, Ligue contre le Cancer (Allocation doctorale to AL), Ligue contre le Cancer (Equipe labellisée 2012), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
TGF-β, Lung Neoplasms, Mice, Nude, Antineoplastic Agents, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transfection, Mice, halofuginone, Piperidines, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, osteosarcoma, Animals, Humans, Neoplasm Metastasis, metastases, bone remodeling, Cell Proliferation, Quinazolinones, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Disease Progression, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, Research Paper
Abstract

International audience; Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-β/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-β/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-β/Smad3 cascade and the response of TGF-β key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination.

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