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1. CRCI2NA inaugural symposium: A meeting on tumor and immune ecosystems.

Author

Guen, Vincent J., André‐Grégoire, Gwennan, Beauvillain, Céline, Boury, Frank, Chauvet, Morgane, Dupuy, Aurore M. M., Fonteneau, Jean‐François, Gagne, Katia, Gavard, Julie, Gomez‐Bougie, Patricia, Grasset, Eloïse, Jardine, Jane, Lamoureux, François, Laurent‐‐Blond, Mélanie, Letouzé, Éric, Macé, Yanis, Maurice, Sandrine, Pecqueur, Claire, Pouliquen, Daniel, and Rbah‐Vidal, Latifa

Subjects
CARCINOGENESIS, BIOLOGY, ECOSYSTEMS, IMMUNOTHERAPY, IMMUNOLOGY
Abstract

The CRCI2NA inaugural symposium, a meeting on tumor and immune ecosystems, took place in the vibrant and picturesque city of Nantes. The meeting gathered world‐renowned experts in cancer biology and immunology. It showcased the most advanced science on mechanisms driving cellular heterogeneity, plasticity, and signaling in normal and cancer cellular ecosystems, which contribute to cancer development, progression, and therapeutic resistance. Recent developments in cancer immunotherapy and anti‐tumor strategies were also discussed to collectively assess new therapeutic vulnerabilities to defeat cancer. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Méthodes de caractérisation génétique des populations végétales - Aide à la construction d'un protocole de renforcement

Author

Ducrettet, Juliette, Maurice, Sandrine, Meslin, Laurence, Imbert, Eric, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Montpellier (UM), FRA, and Institut des Sciences de l'Evolution de Montpellier

Subjects
[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [SDE.MCG]Environmental Sciences/Global Changes, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics
Abstract

Synthèse de méthodologies permettant de caractériser la génétique des populations dans le contexte d'un renforcement sans utiliser d'outils de biologie moléculaire

Published
2022

7. Gestion de la diversité génétique pour la conservation in situ des espèces végétales - Synthèse des principes fondamentaux et préconisations

Author

Imbert, Eric, Ducrettet, Juliette, Maurice, Sandrine, Université de Montpellier (UM), Université de Montpellier (UM), FRA, and Institut des Sciences de l'Evolution de Montpellier

Subjects
[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDE.BE]Environmental Sciences/Biodiversity and Ecology, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics
Published
2021

11. Season‐dependent effect of cleistogamy in Lamium amplexicaule: flower type origin versus inbreeding status.

Author

Stojanova, Bojana, Maurice, Sandrine, and Cheptou, Pierre‐Olivier

Subjects
*FLOWERING of plants, *FLOWERS, *HORSE breeding, *AUTUMN, *POLLINATORS, *REPRODUCTION
Abstract

Premise: Inbreeding depression is traditionally considered a major factor favoring outcrossing in hermaphrodites. Recent experiments have shown that environmental conditions can influence the magnitude of inbreeding depression, but their relevance in natural populations is unclear. To investigate this, we studied the cleistogamous species Lamium amplexicaule, an annual species with individuals experiencing either spring or autumn environmental conditions. In this species, the proportion of cleistogamous/chasmogamous flowers changes according to seasonal cues (e.g., temperature, photoperiod). Our hypothesis was that the plasticity of cleistogamy is an adaptation to seasonal fitness variation in different flower progenies. Methods: To test this hypothesis, we produced the three possible types of progenies through controlled crosses: (1) selfed progeny from cleistogamous flowers; (2) chasmogamous selfed progeny; and (3) chasmogamous outcrossed progeny. Progeny fitness was then measured in a common garden in the two reproduction seasons (autumn and spring). Results: The results showed that season had a major impact on fitness. The fitness of the different progeny types changed across seasons, indicating that the effect of cleistogamy on progeny performance is season‐dependent, consistent with a previous study in a similar environment. Surprisingly, the flower from which the progeny issued (cleistogamous or chasmogamous) had more impact on fitness than the inbred status of the progeny (selfed versus outcrossed), suggesting a potential role of epigenetic processes. Conclusions: The observed patterns of variation were not consistent either with adaptation to environment‐dependent inbreeding depression or to variation in resource availability, but were possibly consistent with adaptation to seasonal pollinator activity. [ABSTRACT FROM AUTHOR]

Published
2020
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12. Patterns of Genome-Wide Nucleotide Diversity in the Gynodioecious Plant Thymus vulgaris Are Compatible with Recent Sweeps of Cytoplasmic Genes.

Author

Mollion, Maeva, Ehlers, Bodil K., Figuet, Emeric, Santoni, Sylvain, Lenormand, Thomas, Maurice, Sandrine, Galtier, Nicolas, and Bataillon, Thomas

Subjects
SEXUAL dimorphism, GENETIC polymorphisms, CYTOPLASMIC male sterility, ANGIOSPERMS, GENOMES
Abstract

Gynodioecy is a sexual dimorphism where females coexist with hermaphrodite individuals. In most cases, this dimorphism involves the interaction of cytoplasmicmale sterility (CMS) genes and nuclear restorer genes. Two scenarios can account for how these interactions maintain gynodioecy. Either CMS genes recurrently enter populations at low frequency via mutation or migration and go to fixation unimpeded (successive sweeps), or CMS genes maintain polymorphism over evolutionary time through interactions with a nuclear restorer allele (balanced polymorphism). To distinguish between these scenarios, we used transcriptome sequencing in gynodioecious Thymus vulgaris and surveyed genome-wide diversity in 18 naturally occurring individuals sampled from populations at a local geographic scale. We contrast the amount and patterns of nucleotide diversity in the nuclear and cytoplasmic genome, and find ample diversity at the nuclear level (π=0.019 at synonymous sites) but reduced genetic diversity and an excess of rare polymorphisms in the cytoplasmic genome relative to the nuclear genome. Our finding is incompatible with the maintenance of gynodioecy via scenarios invoking long-term balancing selection, and instead suggests the recent fixation of CMS lineages in the populations studied. [ABSTRACT FROM AUTHOR]

Published
2018
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13. 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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14. 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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15. Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers?

Author

Morice, Sarah, Danieau, Geoffroy, Rédini, Françoise, Brounais-Le-Royer, Bénédicte, Verrecchia, Franck, 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
[SDV]Life Sciences [q-bio], skeletal development, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, hippo signaling pathway, [SDV] Life Sciences [q-bio], Sonic Hedgehog, [SDV.CAN] Life Sciences [q-bio]/Cancer, osteosarcoma, YAP, Ewing sarcoma, Gli
Abstract

International audience; Osteosarcoma and Ewing sarcoma are the most prevalent bone pediatric tumors. Despite intensive basic and medical research studies to discover new therapeutics and to improve current treatments, almost 40% of osteosarcoma and Ewing sarcoma patients succumb to the disease. Patients with poor prognosis are related to either the presence of metastases at diagnosis or resistance to chemotherapy. Over the past ten years, considerable interest for the Hippo/YAP signaling pathway has taken place within the cancer research community. This signaling pathway operates at different steps of tumor progression: Primary tumor growth, angiogenesis, epithelial to mesenchymal transition, and metastatic dissemination. This review discusses the current knowledge about the involvement of the Hippo signaling pathway in cancer and specifically in paediatric bone sarcoma progression.

Published
2020
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16. TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases 1 development in osteosarcoma model 2 3

Author

Moukengue, Brice, Brown, Hannah, Charrier, Eline, Battaglia, Everine, Baud'Huin, Marc, Quillard, Thibaut, Pham, Therese, Pateras, Ioannis, Gorgoulis, Vassilis, Helleday, Thomas, Heymann, Dominique, Warpman Berglund, Ulrika, Ory, Benjamin, Lamoureux, François, 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 Oncology and Metabolism [Sheffield, UK] (European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Department of Oncology and Metabolism [Sheffield, UK], Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm], National and Kapodistrian University of Athens (NKUA), 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 Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), and maurice, sandrine

Subjects
Osteosarcoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, DNA damage, ROS, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone tumours, MTH1
Abstract

International audience; Background: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor res-ponders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. Methods: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. Findings: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover , 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. Interpretation: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. Funding: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Sant e.

Published
2020
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17. Small animal models for the study of bone sarcoma pathogenesis:characteristics, therapeutic interests and limitations

Author

Nathalie Renema, Dominique Heymann, Frédéric Lézot, Benjamin Ory, Camille Jacques, Carl R. Walkley, Agamemnon E. Grigoriadis, maurice, sandrine, Equipe Labellisée LIGUE 2012 [Nantes], 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 Medicine [Melbourne, Australia] (St. Vincent's Institute of Medical Research), University of Melbourne-St Vincent's Hospital Melbourne [Australia], Centre for Craniofacial and Regenerative Biology [London, UK], King's College London Guy's Hospital [UK], Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], 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), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, This work was supported by the Bone Cancer Research Trust (UK, research project number 144681)., Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes] ( INSERM U1238 ), 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 Medicine [Melbourne, Australia] ( St. Vincent's Institute of Medical Research ), Apoptosis and tumor progression -ATP ( CRCINA - Département ONCO - Equipe 9 ), 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 ) -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 ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, 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
0301 basic medicine, Oncology, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, medicine.medical_treatment, Chondrosarcoma, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, Disease, Bone Sarcoma, lcsh:RC254-282, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, Bone sarcoma, Genetically-engineered mouse models, medicine, Cell-injection, Young adult, Osteosarcoma, [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, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Murine pre-clinical models, Radiation therapy, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sarcoma, lcsh:RC925-935, business, Ewing sarcoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Osteosarcoma, Ewing sarcoma and chondrosarcoma are the three main entities of bone sarcoma which collectively encompass more than 50 heterogeneous entities of rare malignancies. In contrast to osteosarcoma and Ewing sarcoma which mainly affect adolescents and young adults and exhibit a high propensity to metastasise to the lungs, chondrosarcoma is more frequently observed after 40 years of age and is characterised by a high frequency of local recurrence. The combination of chemotherapy, surgical resection and radiotherapy has contributed to an improved outcome for these patients. However, a large number of patients still suffer significant therapy related toxicities or die of refractory and metastatic disease. To better delineate the pathogenesis of bone sarcomas and to identify and test new therapeutic options, major efforts have been invested over the past decades in the development of relevant pre-clinical animal models. Nowadays, in vivo models aspire to mimic all the steps and the clinical features of the human disease as accurately as possible and should ideally be manipulable. Considering these features and given their small size, their conduciveness to experiments, their affordability as well as their human-like bone-microenvironment and immunity, murine pre-clinical models are interesting in the context of these pathologies. This chapter will provide an overview of the murine models of bone sarcomas, paying specific attention for the models induced by inoculation of tumour cells. The genetically-engineered mouse models of bone sarcoma will also be summarized. Keywords: Bone sarcoma, Osteosarcoma, Ewing sarcoma, Chondrosarcoma, Cell-injection, Murine pre-clinical models, Genetically-engineered mouse models

Published
2018
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18. 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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19. 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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20. 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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21. Mesenchymal stem cells increase proliferation but do not change quiescent state of osteosarcoma cells: Potential implications according to the tumor resection status

Author

Philippe Rosset, Pierre Perrot, Pierre Avril, Louis-Romée Le Nail, Dominique Heymann, Pierre Layrolle, Meadhbh Á. Brennan, Gonzague de Pinieux, Valérie Trichet, 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 Traumatologique 2 [CHRU Tours], Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Chirurgie Plastique et des Brulés [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by INSERM, the 'Ligue Contre le Cancer' (Equipe Labellisée LIGUE 2012, grant EL2012NCC/DH), 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('appel à projet 2013')., Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université Francois Rabelais [Tours], and maurice, sandrine

Subjects
0301 basic medicine, musculoskeletal diseases, Pathology, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, Osteolysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell cycle, Quiescence, lcsh:RC254-282, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Osteoclast, Medicine, Mesenchymal stem cell, [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, business.industry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Oncology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Adipose tissue transfer, 030220 oncology & carcinogenesis, Sarcoma, lcsh:RC925-935, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Paper
Abstract

Conventional therapy of primary bone tumors includes surgical excision with wide resection, which leads to physical and aesthetic defects. For reconstruction of bone and joints, allografts can be supplemented with mesenchymal stem cells (MSCs). Similarly, adipose tissue transfer (ATT) is supplemented with adipose-derived stem cells (ADSCs) to improve the efficient grafting in the correction of soft tissue defects. MSC-like cells may also be used in tumor-targeted cell therapy. However, MSC may have adverse effects on sarcoma development. In the present study, human ADSCs, MSCs and pre-osteoclasts were co-injected with human MNNG-HOS osteosarcoma cells in immunodeficient mice. ADSCs and MSCs, but not the osteoclast precursors, accelerated the local proliferation of MNNG-HOS osteosarcoma cells. However, the osteolysis and the metastasis process were not exacerbated by ADSCs, MSCs, or pre-osteoclasts. In vitro proliferation of MNNG-HOS and Saos-2 osteosarcoma cells was increased up to 2-fold in the presence of ADSC-conditioned medium. In contrast, ADSC-conditioned medium did not change the dormant, quiescent state of osteosarcoma cells cultured in oncospheres. Due to the enhancing effect of ADSCs/MSCs on in vivo/in vitro proliferation of osteosarcoma cells, MSCs may not be good candidates for osteosarcoma-targeted cell therapy. Although conditioned medium of ADSCs accelerated the cell cycle of proliferating osteosarcoma cells, it did not change the quiescent state of dormant osteosarcoma cells, indicating that ADSC-secreted factors may not be involved in the risk of local recurrence., Graphical abstract fx1

Published
2016
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22. 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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23. Vertical Bone Regeneration with Synthetic Biomimetic Calcium Phosphate onto the Calvaria of Rats

Author

Maria-Pau Ginebra, Carlos Aparicio, Pierre Layrolle, Borhane H. Fellah, Yassine Maazouz, David Pastorino, Gonzague de Pinieux, Alain Hoornaert, 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), Mimetis Biomaterials, Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Biomaterials, Biomechanics and Tissue Engineering Group, Universitat Politècnica de Catalunya [Barcelona] (UPC), Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica, Universitat Politècnica de Catalunya. BBT - Biomaterials, Biomecànica i Enginyeria de Teixits, Inserm, University of Minnesota School of Dentistry, maurice, sandrine, 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 École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)

Subjects
Calcium Phosphates, Male, Bone Regeneration, calvaria, Ossos -- Regeneració, Biomedical Engineering, Medicine (miscellaneous), chemistry.chemical_element, Bioengineering, Calvaria, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Calcium, synthetic biomimetic calcium phosphate, Enginyeria dels materials [Àrees temàtiques de la UPC], Hydroxyapatite, Hidroxiapatita, 03 medical and health sciences, vertical bone regeneration, 0302 clinical medicine, Biomimetics, medicine, Animals, Rats, Wistar, Bone regeneration, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, deproteinized bovine bone matrix, 030304 developmental biology, 0303 health sciences, vertical bone regeneration synthetic biomimetic calcium phosphate deproteinized bovine bone matrix hydroxyapatite cups calvaria rats, Chemistry, Skull, hydroxyapatite, 030206 dentistry, Rats, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, stomatognathic diseases, medicine.anatomical_structure, Calcium phosphate, rats Impact Statement, Bone Substitutes, Ridge (meteorology), Fosfat de calci, cups, Biomedical engineering
Abstract

International audience; Bone regeneration is often required to provide adequate oral rehabilitation before dental implants. Vertical ridge augmentation is the most challenging of all situations, and often requires the use of autologous bone grafting. However, autologous bone grafting induces morbidity, and the harvestable bone is limited in quantity. Alternatives to autologous bone grafting include bovine-bone-derived biomaterials, which provide good clinical results and synthetic bone substitutes that still fail to provide a reliable clinical outcome. Synthetic biomimetic calcium phosphate (SBCP) biomaterials, consisting of precipitated apatite crystals that resemble in composition and crystallinity to the mineral phase of bone, arise as alternatives to both bovine bone and the current sintered bone substitutes. This study aims to compare the vertical bone regeneration capacity of the SBCP (MimetikOss, Mimetis Biomaterials) with that of a deproteinized bovine bone matrix (DBBM, Bio-Oss Ò ; Geistlich Biomaterials) on the calvaria of rats. To model vertical bone augmentation, hemispherical cups were filled with the two types of biomaterial granules and implanted onto the skull of rats, while empty cups were used as controls. After 4 and 8 weeks of healing, bone growth was determined by microcomputed tomography and histomorphometry. After 4 weeks of implantation, a significantly higher bone growth was found in the case of SBCP compared with DBBM and left empty controls. At 8 weeks, no statistically significant differences were found between the two bone substitutes. These results are promising since vertical bone regeneration was faster in the case of SBCP than for DBBM.

Published
2019
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24. 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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25. The Intrinsic and Extrinsic Implications of RANKL/RANK Signaling in Osteosarcoma: From Tumor Initiation to Lung Metastases

Author

Benjamin Navet, Kosei Ando, Jorge William Vargas-Franco, Régis Brion, Jérome Amiaud, Kanji Mori, Hideo Yagita, Christopher G. Mueller, Franck Verrecchia, Clotilde Dumars, Marie-Françoise Heymann, Dominique Heymann, Frédéric Lézot, 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), 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 Basic Studies [Medellin, AA, Colombia], University of Antioquia [Medellin, AA, Colombia], Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, Juntendo University School of Medicine, Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie des Cancers et de Théranostic [St Herblain, Nantes] (LabCT), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, B.N. is a grant-holder of the French Ministry for Higher Education and Research. K.A. is a grant-holder of the Région des Pays de la Loire (France). C.D. received a fellowship from INSERM. We would also like to thank the Cancer biobank 'Tumorothèque IRCNA' (Nantes University Hospital–Institut de Cancérologie de l’Ouest–Saint-Herblain–F44800–France). This study was supported by the Ligue Nationale Contre le Cancer (Equipe LIGUE 2012 (D.H.) and Ligue 44 (F.L.)), the Institut National du Cancer (INCa research project number 6001) and the Bone Cancer Research Trust, UK (research project number 144681)., Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and maurice, sandrine

Subjects
musculoskeletal diseases, T-lymphocyte, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, bone, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, osteosarcoma, RANKL/RANK, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, metastases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background: Osteosarcoma is the most frequent form of malignant pediatric bone tumor. Despite the current therapeutic arsenal, patient life-expectancy remains low if metastases are detected at the time of diagnosis, justifying research into better knowledge at all stages of osteosarcoma ontogenesis and identification of new therapeutic targets. Receptor Activator of Nuclear factor &kappa, B (RANK)expression has been reported in osteosarcoma cells, raising the question of Receptor Activator of Nuclear factor &kappa, B Ligand (RANKL)/RANK signaling implications in these tumor cells (intrinsic), in addition to previously reported implications through osteoclast activation in the tumor microenvironment (extrinsic). Methods: Based on in vitro and in vivo experimentations using human and mouse osteosarcoma cell lines, the consequences on the main cellular processes of RANK expression in osteosarcoma cells were analyzed. Results: The results revealed that RANK expression had no impact on cell proliferation and tumor growth, but stimulated cellular differentiation and, in an immune-compromised environment, increased the number of lung metastases. The analysis of RANKL, RANK and osteoprotegerin (OPG) expressions in biopsies of a cohort of patients revealed that while RANK expression in osteosarcoma cells was not significantly different between patients with or without metastases at the time of diagnosis, the OPG/RANK ratio decreased significantly. Conclusion: Altogether, these results are in favor of RANKL-RANK signaling inhibition as an adjuvant for the treatment of osteosarcoma.

Published
2018
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26. Maternal RANKL Reduces the Osteopetrotic Phenotype of Null Mutant Mouse Pups

Author

Navet, Benjamin, Vargas-Franco, Jorge, Gama, Andrea, Amiaud, Jerome, Choi, Yongwon, Yagita, Hideo, Mueller, Christopher, Rédini, Françoise, Heymann, Dominique, Castaneda, Beatriz, Lézot, Frédéric, 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 Basic Studies [Medellin, AA, Colombia], University of Antioquia [Medellin, AA, Colombia], Complications vasculaires du diabète (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Department of Immunology [Tokyo, Japan], Juntendo University School of Medicine, Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), European Associated Laboratory [Sheffield, UK] (Sarcoma Research Unit), The University of Sheffield [Sheffield, U.K.], Laboratoire de Biologie des Cancers et de Théranostic (LabCT), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), 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), The project received the financial support of the French National Cancer Institute (Funding INCa-6001). B.N. has received a grant from the French Ministry for Higher Education and Research. A.G. is a grantee of INSERM-SFODF., maurice, sandrine, University of Pennsylvania, 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
musculoskeletal diseases, mandible, [SDV.CAN] Life Sciences [q-bio]/Cancer, lcsh:R, osteoclast, RANKL, lcsh:Medicine, morphogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, tooth, bone, Article, skeletal growth
Abstract

RANKL signalization is implicated in the morphogenesis of various organs, including the skeleton. Mice invalidated for Rankl present an osteopetrotic phenotype that was less severe than anticipated, depending on RANKL’s implication in morphogenesis. The hypothesis of an attenuated phenotype, as a result of compensation during gestation by RANKL of maternal origin, was thus brought into question. In order to answer this question, Rankl null mutant pups from null mutant parents were generated, and the phenotype analyzed. The results validated the presence of a more severe osteopetrotic phenotype in the second-generation null mutant with perinatal lethality. The experiments also confirmed that RANKL signalization plays a part in the morphogenesis of skeletal elements through its involvement in cell-to-cell communication, such as in control of osteoclast differentiation. To conclude, we have demonstrated that the phenotype associated with Rankl invalidation is attenuated through compensation by RANKL of maternal origin.

Published
2018
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27. Early fracture healing is delayed in the Col1a2+/G610C osteogenesis imperfecta murine model

Author

Valérie Trichet, Séverine Battaglia, Pierre Layrolle, Roberta Besio, Simona Villani, Silvia Maruelli, Laura Leoni, Antonio Rossi, Antonella Forlino, Department of Molecular Medicine [Pavia, Italy] (Unit of Biochemistry), University of Pavia, 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 Public Health and Experimental and Forensic Medicine [Pavia, Italy] (Unit of Biostatistics and Clinical Epidemiology), Università degli Studi di Pavia, The work was supported by Care4BrittleBone (2015-0003) and the European Community, FP7, ‘Sybil’ project (Grant No. 602300)., European Project: 602300,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,SYBIL(2013), maurice, sandrine, Systems biology for the functional validation of genetic determinants of skeletal diseases - SYBIL - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602300 - VALID, and Università degli Studi di Pavia = University of Pavia (UNIPV)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Type II collagen, 030209 endocrinology & metabolism, Bone healing, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Callus, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, medicine, Hyperplastic callus formation, Cartilaginous Tissue, Orthopedics and Sports Medicine, µCT, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Fracture repair, business.industry, Cartilage, Bone fracture, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Osteogenesis imperfecta, Collagen, business, Type I collagen, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Osteogenesis imperfecta (OI) is a rare heritable skeletal dysplasia mainly caused by type I collagen abnormalities and characterized by bone fragility and susceptibility to fracture. Over 85% of the patients carry dominant mutations in the genes encoding for the collagen type I α1 and α2 chains. Failure of bone union and/or presence of hyperplastic callus formation after fracture were described in OI patients. Here we used the Col1a2+/G610C mouse, carrying in heterozygosis the α2(I)-G610C substitution, to investigate the healing process of an OI bone. Tibiae of 2-month-old Col1a2+/G610C and wild-type littermates were fractured and the healing process was followed at 2, 3, and 5 weeks after injury from fibrous cartilaginous tissue formation to its bone replacement by radiography, micro-computed tomography (µCT), histological and biochemical approaches. In presence of similar fracture types, in Col1a2+/G610C mice an impairment in the early phase of bone repair was detected compared to wild-type littermates. Smaller callus area, callus bone surface, and bone volume associated to higher percentage of cartilage and lower percentage of bone were evident in Col1a2+/G610C at 2 weeks post fracture (wpf) and no change by 3 wpf. Furthermore, the biochemical analysis of collagen extracted from callus 2 wpf revealed in mutants an increased amount of type II collagen, typical of cartilage, with respect to type I, characteristic of bone. This is the first report of a delay in OI bone fracture repair at the modeling phase.

Published
2018
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28. 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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29. Transforming Growth Factor-β Signaling Plays a Pivotal Role in the Interplay Between Osteosarcoma Cells and Their Microenvironment

Author

Verrecchia, Franck, Rédini, Françoise, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes] ( INSERM U1238 ), 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 ), This work was supported by the associations 'Etoile de Martin' and 'Imagine for Margo,' and by SFCE, the 'Societe Française de lutte contre les cancers et leucemies de l’enfant et l’adolescent,' and the Fédération Enfant et Santé., 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), 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
[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.CAN]Life Sciences [q-bio]/Cancer, transforming growth factor-β, Review, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, bone, microenvironment, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Oncology, osteosarcoma, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, metastases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Osteosarcomas are the most frequent form of primary bone tumors and mainly affect children, adolescents, and young adults. Despite encouraging progress in therapeutic management, including the advent of multidrug chemotherapy, the survival rates have remained unchanged for more than four decades: 75% at 5 years for localized disease, but two groups of patients are still at high risk: metastatic at diagnosis (overall survival around 40% at 5 years) and/or poor responders to chemotherapy (20% at 5 years). Because these tumors are classified as " complex genomic, " it is extremely difficult to determine the signaling pathways that might be targeted by specific therapies. A hypothesis has thus emerged, stating that the particular microenvironment of these tumors may interfere with the tumor cells that promote chemoresistance and the dissemination of metastases. The stroma is composed of a large number of cell types (immune cells, endothelial cells, mesenchymal stromal cells, etc.) which secrete growth factors, such as transforming growth factor-β (TGF-β), which favors the development of primary tumors and dissemination of metastases by constituting a permissive niche at primary and distant sites. Rather than targeting the tumor cells themselves, which are very heterogeneous in osteosarcoma, the hypothesis is instead to target the key actors secreted in the microenvironment, such as TGF-βs, which play a part in tumor progression. In the last decade, numerous studies have shown that overexpression of TGF-β is a hallmark of many cancers, including primary bone tumors. In this context, TGF-β signaling has emerged as a crucial factor in the cross talk between tumor cells and stroma cells in poor-prognosis cancers. Secretion of TGF-β by tumor cells or stroma cells can effectively act in a paracrine manner to regulate the phenotype and functions of the microenvironment to stimulate protumorigenic microenvironmental changes. TGF-β can thus exert its protumorigenic function in primary bone tumors by promoting angiogenesis, bone remodeling and cell migration, and by inhibiting immu-nosurveillance. This review focuses on the involvement of TGF-β signaling in primary bone tumor development, and the related therapeutic options that may be possible for these tumors.

Published
2018
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30. 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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31. 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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32. 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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33. 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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34. 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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35. 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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36. 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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37. Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma

Author

Georges, S., Calleja, L. R., Jacques, C., Lavaud, M., Moukengue, B., Lecanda, F., Quillard, T., Gabriel, M. T., Cartron, P. -F, Baud Huin, M., Lamoureux, F., Dominique Heymann, Ory, B., 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), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Département de recherche en cancérologie, Université de Nantes (UN)-IFR26, Equipe LIGUE Nationale Contre le Cancer 2012, 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)-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), Laboratoire de Biologie des Cancers et de Théranostic [St Herblain, Nantes] (LabCT), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, maurice, sandrine, Adhesion and Metastasis Laboratory [Navarra, Spain] (Division of Oncology ), University Clinic of Navarra - CUN [Pamplona, Spain]-Center for Applied Medic al Research [Navarra, Spain], Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], 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), Réseau Epigénétique du Cancéropôle Grand-Ouest [Nantes] (REpiCGO), Cancéropôle Grand Ouest [Nantes]-Maison de la Recherche en Santé [Nantes], Thanks for the financial support of Région pays de la loire, Ligue contre le cancer, SFCE, Etoile de martin, Fondation ARC., Bernardo, Elizabeth, Center for Applied Medic al Research [Navarra, Spain]-University Clinic of Navarra - CUN [Pamplona, Spain], 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
[SDV.CAN] Life Sciences [q-bio]/Cancer, osteosarcoma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], metastasis, [SDV.CAN]Life Sciences [q-bio]/Cancer, C-Met, Research Paper, microRNAs
Abstract

International audience; The metastatic dissemination is a complex multistep process by which tumor cells from a primary site enter into the systemic circulation to finally spread at distant sites. Even if this mechanism is rare at the tumor level, it remains the major cause of Osteosarcoma-patients' relapse and mortality. MicroRNAs (miRNAs) have recently been described as novel epigenetics' genes' expression regulators actively implicated in cancer progression and dissemination. The understanding of their implication in the metastatic spreading could help clinicians to improve the outcome of osteosarcoma. We established the miRNA's expression-profile between primary bone-tumors (PTs), circulating tumor cells (CTCs) and lung metastatic (META) samples from in vivo mice xenograft models. Our results show that the expression level of the miR-198 and-206 was decreased in META samples, in which the expression of the metastasis-related receptor C-Met was up-regulated. Those expression variations were validated in osteosarcoma patient biopsies from matching primary tumors and lung metastasis. We validated in vitro the endogenous miRNAs inhibitory effects on both migration and invasion, as well as we confirmed by luciferase assays that the C-Met receptor is one of their bona-fide targets. The anti-metastatic effect of these miRNAs was also validated in vivo, as their direct injections into the tumors reduce the number of lung-metastases and prolongs the overall survival of the treated animals. All together, our results suggest the absence of the miR-198 and-206 as powerful predictive biomarkers of the tumor cell dissemination and the rationale of their potential therapeutic use in the treatment of Osteosarcoma.

Published
2018
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38. PARADOXICAL SIDE EFFECTS OF BISPHOSPHONATES ON THE SKELETON: WHAT DO WE KNOW AND WHAT CAN WE DO? †

Author

Vargas-Franco, Jorge, Castaneda, Beatriz, Rédini, Françoise, Francisco Gómez, David, Heymann, Dominique, Lezot, Frederic, maurice, sandrine, Department of Basic Studies [Medellin, AA, Colombia], University of Antioquia [Medellin, AA, Colombia], Micro environnement des tumeurs osseuses primitives : signalisation et ciblage thérapeutique (U1238 Inserm / Equipe 1), 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)-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 de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), and The University of Sheffield [Sheffield, U.K.]

Subjects
side effects, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, skeleton, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bisphosphonates
Abstract

International audience; Bisphosphonates are considered the most effective drugs for controlling adult and pediatric osteolytic diseases. Although they have been used successfully for many years, several side effects, such as osteonecrosis of the jaw, delayed dental eruption, atypical femoral fracture and alterations to the bone growth system, have been described. After an overview of nitrogenous bisphosphonate, the purpose of this article is to describe their mechanisms of action and current applications, review the preclinical and clinical evidence of their side effects in the skeleton ("what we know"), and describe current recommendations for preventing and managing these effects ("what we can do"). Finally, promising future directions on how to limit the occurrence of these side effects will be presented. This article is protected by copyright. All rights reserved.

Published
2018
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39. Mimicking the Biochemical and Mechanical Extracellular Environment of the Endochondral Ossification Process to Enhance the In Vitro Mineralization Potential of Human Mesenchymal Stem Cells

Author

Peter Owens, Fiona E. Freeman, Pierre Layrolle, Laoise M. McNamara, Jessica Schiavi, Meadhbh Á. Brennan, Centre for Biomechanics Research -BMEC [Galway, Ireland], National University of Ireland [Galway] (NUI Galway), 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), Centre for Microscopy and Imaging - CMI [Galway, Ireland], European Project: 258992,EC:FP7:ERC,ERC-2010-StG_20091028,BONEMECHBIO(2011), European Project: 241879,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,REBORNE(2010), maurice, sandrine, Frontier research in bone mechanobiology during normal physiology, disease and for tissue regeneration - BONEMECHBIO - - EC:FP7:ERC2011-02-01 - 2016-01-31 - 258992 - VALID, Regenerating Bone defects using New biomedical Engineering approaches - REBORNE - - EC:FP7:HEALTH2010-01-01 - 2015-06-30 - 241879 - 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 la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0301 basic medicine, 0206 medical engineering, Hydrostatic pressure, Biomedical Engineering, Bioengineering, 02 engineering and technology, Biochemistry, osteogenesis, Biomaterials, 03 medical and health sciences, In vivo, medicine, Extracellular, mechanical stimulation, chondrogenic priming, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Endochondral ossification, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, mesenchymal stem cells, Chemistry, Cartilage, Mesenchymal stem cell, Chondrogenesis, 020601 biomedical engineering, In vitro, Cell biology, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, 030104 developmental biology, medicine.anatomical_structure, endochondral ossification, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, hydrostatic pressure, Biomedical engineering
Abstract

International audience; Chondrogenesis and mechanical stimulation of the cartilage template are essential for bone formation through the endochondral ossification process in vivo. Recent studies have demonstrated that in vitro regeneration strategies that mimic these aspects separately, either chondrogenesis or mechanical stimulation, can promote mineralization to a certain extent both in vitro and in vivo. However, to date no study has sought to incorporate both the formation of the cartilage template and the application of mechanical stimulation simultaneously to induce osteogenesis. In this study, we test the hypothesis that mimicking both the biochemical and mechanical extracellular environment arising during endochondral ossification can enhance the in vitro mineralization potential of human mesenchymal stem cells (hMSCs). hMSC aggregates were cultured for 21 days under the following culture conditions; (1) Growth Medium-hydrostatic pressure (HP), (2) Chondrogenic Priming–HP, (3) Growth Medium + HP, and (4) Chondrogenic Priming +HP. Each group was then further cultured for another 21 days in the presence of osteogenic growth factors without HP. Biochemical (DNA, sulfate glycosaminoglycan, hydroxyproline, alkaline phosphatase activity, and calcium), histological (Alcian Blue and Alizarin Red), and immunohistological (Col I, II, and X, and BSP-2) analyses were conducted to investigate chondrogenic and osteogenic differentiation at various time points (14, 21, 35, and 42 days). Our results showed the application of HP-induced chondrogenesis similar to that of chondrogenic priming, but interestingly, there was a reduction in hypertrophy markers (collagen type X) by applying HP alone versus chon-drogenic priming alone. Moreover, the results showed that both chondrogenic priming and HP in tandem during the priming period, followed by culture in osteogenic medium, accelerated the osteogenic potential of hMSCs.

Published
2017
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40. 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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41. 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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42. Impact of biomaterial microtopography on bone regeneration: comparison of three hydroxyapatites

Author

Pierre Layrolle, Eric Rompen, Miljana Bacevic, Peter Schupbach, Pierre Drion, Department of Periodontology and Oral Surgery [Liège, Belgium], Université de Liège, Dental Biomaterials Research Unit - d-BRU [Liège, Belgium], 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), School of Medicine [Philadelphia, PA, USA] (University of Pennsylvania), University of Pennsylvania [Philadelphia], Central Animal Facility [Liège, Belgium] (Giga-R), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), University of Pennsylvania School of Veterinary Medicine, and maurice, sandrine

Subjects
Male, medicine.medical_specialty, Surface Properties, 0206 medical engineering, Sinus lift, Biocompatible Materials, 02 engineering and technology, 03 medical and health sciences, 0302 clinical medicine, bone regeneration, Specific surface area, medicine, Animals, Hydroxyapatites, Electronic microscopy, Bone regeneration, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Minerals, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Manufacturing process, Chemistry, surface characteristics, Biomaterial, hydroxyapatite, 030206 dentistry, 020601 biomedical engineering, Surgery, Durapatite, osteoconduction, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Bone Substitutes, Rabbits, Oral Surgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomedical engineering
Abstract

International audience; 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.

Published
2017
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43. 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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44. CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: An immunohistochemical analysis of the biopsies fromthe French OS2006 phase 3 trial

Author

Françoise Rédini, Marta Jimenez, Corinne Bouvier, Claire Illac, Laurence Brugieres, Véronique Minard, Béatrice Marie, Vincent Minville, Gonzague de Pinieux, François Gouin, Marie-cecile Ledeley, Julia Gilhodes, Thomas Filleron, Sophie Piperno-Neumann, Natacha Entz-Werle, Frédérique Larousserie, Eric Mascard, Anne Gomez-Brouchet, Jean-Marc Guinebretière, Sébastien Aubert, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Unité de Biostatistiques [Toulouse], Institut Claudius Regaud-Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Pathologie [Institut Curie], Institut Curie [Paris], Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pathologie [AP-HP Hôpital Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'Oncologie Pédiatrique [CHU Hautepierre, Strasbourg], Hôpital de Hautepierre [Strasbourg], 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 Pathologie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie orthopédique et traumatologie pédiatrique [CHU Necker ], CHU Necker - Enfants Malades [AP-HP], Département d'Orthopédie [CHU Hôtel Dieu, Nantes], Hôtel-Dieu de Nantes, UNICANCER [Paris], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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 Médicale [Institut Curie, Paris], Funding were obtained from the French National Cancer Institute (INCa Novartis Chugai Ligue Nationale contre le Cancer Fédération Enfants et Santé Société Française des Cancers et Leucémies de l’enfant (SFC and the Association Etoile de Martin). The ancillary biological studies were approved by the Sarcoma Group of UNICANCER, the 'Groupe des Sarcomes Français-Groupe d’étude des Tumeurs Osseuses' (GSF-GETO), the SFCE and the InterSarc network., Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT)-Institut Claudius Regaud, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), 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)-Université Toulouse III - Paul Sabatier (UT3), 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), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), maurice, sandrine, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Oncology, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Pathology, medicine.medical_treatment, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, cd163, lcsh:RC254-282, Metastasis, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, osteosarcoma, Immunology and Allergy, Medicine, Cytotoxic T cell, Original Research, Chemotherapy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, CD68, cd8, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, macrophages, 030104 developmental biology, pd1/pdl-1 checkpoint, 030220 oncology & carcinogenesis, Immunohistochemistry, Osteosarcoma, business, lcsh:RC581-607, CD163, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; The French phase 3 trial (OS 2006) testing zoledronic acid, an osteoclast inhibitor, with chemotherapy and surgery did not improve the outcome of patients with osteosarcoma (OS). To understand this unexpected result, the presence of infiltrating immune cells was investigated in 124 pre-therapeutic biopsies of patients enrolled in the trial. The percentage of CD68/CD163 tumor-infiltrating macrophages (TAMs), CD8+ lymphocytes, osteoclasts, and the PD1/PDL-1 checkpoint were assessed by immunohistochemistry. M1/M2 macrophage polarization was characterized by pSTAT1/CMAF staining. The expression of these biomarkers was correlated with clinical outcome. No statistical correlations were found with response to chemotherapy. High CD163 levels (>50% of cells per core; 43.8% of patients) were associated with CMAF nuclear expression and significantly correlated with better overall survival (p = 0.0025) and longer metastasis progression-free survival (MPFS, p = 0.0315) independently of metastatic status (p = 0.002). Only a trend was observed for patients with high CD68-positive cells (p = 0.0582). CD8+ staining was positive in >50% of cases with a median staining of 1%. Lower CD8+ levels were associated with metastatic disease at diagnosis and the presence of CD8-positive cells significantly correlated with improved overall survival in zoledronate-treated patients (p = 0.0415). PD1/PDL-1 staining was negative in >80% of cases and was not correlated with outcome. Finally, CD163-positive TAMs and CD8 positive cells are crucial prognostic biomarkers in OS, whereas PD1/PDL-1 checkpoint plays a minor role. For the first time, we described a correlation between CD8 positive cells and survival in zoledronate-treated patients. The immunohistochemical analysis of the microenvironment in biopsies may represent a novel tool for therapeutic stratification.

Published
2017
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45. 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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46. Changes of Bone Turnover Markers in Long Bone Nonunions Treated with a Regenerative Approach

Author

Donatella Granchi, Gabriela Ciapetti, Enrique Gómez-Barrena, Philippe Rosset, Pierre Layrolle, Markus Rojewski, Benedetta Spazzoli, Davide Maria Donati, Orthopedic Pathophysiology and Regenerative Medicine Unit [Bologna, Italy], Rizzoli Orthopedic Institute [Bologna, Italy], Instituto de Investigacion Hospital La Paz (IdiPAZ), Foundation for Biomedical Research, Hospital Universitario La Paz [Madrid, Spain]-Hospital Universitario La Paz [Madrid, Spain]-Hospital Universitario La Paz-School of Nursing Building, Institute for Clinical Transfusion Medicine and Immunogenetic Ulm [Ulm, Germany], Institut für Klinische Transfusionsmedizin und Immungenetik Ulm -IKT [Ulm, Germany], Service de chirurgie orthopédique et de traumatologie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), III Orthopedic and Traumatology Clinic [Bologna, Italy], Department of Biomedical and Neuromotor Sciences [Bologna, Italy], University of Bologna, Italian Ministry of Health, Ricerca Corrente, project 'Strategie di rigenerazione ossea: dall’interazione materiale/cellule dell’osso ai markers riparativi' (2013–2016)., European Project: 241879,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,REBORNE(2010), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), University of Bologna/Università di Bologna, maurice, sandrine, Regenerating Bone defects using New biomedical Engineering approaches - REBORNE - - EC:FP7:HEALTH2010-01-01 - 2015-06-30 - 241879 - VALID, UAM. Departamento de Cirugía, Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Granchi, Donatella, Gómez-Barrena, Enrique, Rojewski, Marku, Rosset, Philippe, Layrolle, Pierre, Spazzoli, Benedetta, Donati, Davide Maria, and Ciapetti, Gabriela

Subjects
0301 basic medicine, lcsh:Internal medicine, Pathology, medicine.medical_specialty, Article Subject, Medicina, Long bone, Nonunion, Urology, Bone healing, Bone resorption, Biphasic calcium phosphate, Bone remodeling, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Osteoclast, medicine, lcsh:RC31-1245, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Molecular Biology, 030222 orthopedics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Cell Biology, medicine.disease, Changes, 3. Good health, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, 030104 developmental biology, medicine.anatomical_structure, Bone turnover markers (BTM), Bone nonunions, Alkaline phosphatase, Regenerative treatment, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

In this clinical trial, we investigated if biochemical bone turnover markers (BTM) changed according to the progression of bone healing induced by autologous expanded MSC combined with a biphasic calcium phosphate in patients with delayed union or nonunion of long bone fractures. Bone formation markers, bone resorption markers, and osteoclast regulatory proteins were measured by enzymatic immunoassay before surgery and after 6, 12, and 24 weeks. A satisfactory bone healing was obtained in 23 out of 24 patients. Nine subjects reached a good consolidation already at 12 weeks, and they were considered as the "early consolidation" group. We found that bone-specific alkaline phosphatase (BAP), C-terminal propeptide of type I procollagen (PICP), and beta crosslaps collagen (CTX) changed after the regenerative treatment, BAP and CTX correlated to the imaging results collected at 12 and 24 weeks, and BAP variation along the healing course differed in patients who had an "early consolidation." A remarkable decrease in BAP and PICP was observed at all time points in a single patient who experienced a treatment failure, but the predictive value of BTM changes cannot be determined. Our findings suggest that BTM are promising tools for monitoring cell therapy efficacy in bone nonunions, but studies with larger patient numbers are required to confirm these preliminary results, This work was supported by the EC, Seventh Framework Program (FP7), through the REBORNE Project, Grant Agreement no. 241879 and partially by the Italian Ministry of Health, Ricerca Corrente, project “Strategie di rigenerazione ossea: dall’interazione materiale/cellule dell’osso ai markers riparativi” (2013–2016)

Published
2017
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47. 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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48. 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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49. Proteoglycan-targeting applied to hypoxia-activated prodrug therapy in chondrosarcoma: first proof-of-concept

Author

Voissiere, Aurélien, Weber, Valérie, Gerard, Yvain, Rédini, Françoise, Raes, Florian, Chezal, Jean-Michel, Degoul, Françoise, Peyrode, Caroline, Miot-Noirault, Elisabeth, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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), Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), Centre d'Imagerie du Petit Animal (CIPA), Université d'Orléans (UO), Ligue contre le cancer, PRT-k, Translational Cancer Research: INCa-DGOS, D-TECT project reference R15066CC / RPT15003CCA., and maurice, sandrine

Subjects
chondrosarcoma, proteoglycan, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], hypoxia-activated prodrug, extracellular matrix, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], quaternary ammonium, [SDV.CAN]Life Sciences [q-bio]/Cancer, Research Paper
Abstract

International audience; Due to its abundant chondrogenic matrix and hypoxic tissue, chondrosarcoma is chemo-and radio-resistant. Our group has developed a proteoglycan targeting strategy by using a quaternary ammonium (QA) function as a carrier of DNA alkylating agents to chondrosarcoma environment. Here, we assessed the relevance of this strategy applied to hypoxia-activated prodrugs, by conjugating a QA to 2-nitroimidazole phosphoramidate. This derivative, named as 8-QA, was evaluated respectively to its non-QA equivalent and to a QA-conjugated but non-hypoxia activated. Firstly binding to aggrecan was confirmed from dissociation constant determined by Surface Plasmon Resonance. In vitro, in HEMC-SS chondrosarcoma cells cultured in monolayer and in spheroids, 8-QA showed higher cytotoxic activity in hypoxia versus normoxia, and led to a strong accumulation of cells in S phase and apoptosis. In vivo, a HEMC-SS xenograft model was implanted on SCID mice and characterized for hypoxia by photoacoustic imaging as well as proteoglycan content. When HEMC-SS bearing mice were given 8-QA at 47 μmol/kg according to a q4d x 6 schedule, a significant 62.1% inhibition of tumor growth was observed, without associated hematological side effects. Mechanistic studies of treated tumors highlighted decrease in mitotic index associated to increase in both p21 and p53S15 markers. Interestingly, 8-QA treatment induced an increase of DNA damages as measured by γH2AX predominantly found in pimonidazole-positive hypoxic areas. These preclinical results are the first to demonstrate the interest of addressing hypoxia-activated prodrugs selectively to proteoglycan of chondrogenic tumor tissue, as a promising therapeutic strategy.

Published
2017
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50. 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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