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11 results on '"MESH: Osteopontin"'

1. New role of osteopontin in DNA repair and impact on human glioblastoma radiosensitivity

Author

Philippe Delvenne, Andrei Turtoi, Nicolas Goffart, Elettra Bianchi, Patrick Roncarati, Olivier Peulen, Marie-Julie Nokin, Akeila Bellahcene, Bernard Rogister, Natacha Leroi, Vincenzo Castronovo, Arnaud Blomme, Félix Scholtes, François Lallemand, Aurélie Henry, Yvette Habraken, Philippe Martinive, Paul Peixoto, Jérémy Lambert, Université de Liège, Centre Hospitalier Universitaire de Liège (CHU-Liège), University Medical Center [Utrecht], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Herrada, Anthony

Subjects
0301 basic medicine, osteopontin, DNA Repair, MESH: Osteopontin, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: DNA Breaks, Double-Stranded, Mice, SCID, Radiation Tolerance, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, MESH: RNA, Small Interfering, DNA damage repair, Medicine, MESH: Animals, MESH: Gene Silencing, DNA Breaks, Double-Stranded, Osteopontin, MESH: Mice, SCID, Phosphorylation, RNA, Small Interfering, MESH: DNA Repair, Gene knockdown, MESH: Radiation Tolerance, biology, Brain Neoplasms, MESH: Glioblastoma, Recombinant Proteins, radioresistance, Oncology, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Comet Assay, Research Paper, EGFRvIII, MESH: Cell Line, Tumor, DNA repair, Mice, Nude, MESH: Comet Assay, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, stomatognathic system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cell Line, Tumor, Radioresistance, Glioma, MESH: Mice, Nude, Animals, Humans, Gene Silencing, Radiosensitivity, Clonogenic assay, MESH: Mice, MESH: Humans, MESH: Phosphorylation, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, glioblastoma, medicine.disease, nervous system diseases, 030104 developmental biology, Cell culture, biology.protein, Cancer research, business, MESH: Female, MESH: Neoplasm Transplantation, Neoplasm Transplantation
Abstract

International audience; Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness characters and tumorigenicity of glioma initiating cells. Consultation of publicly available TCGA database indicated that high OPN expression correlated with poor survival in GBM patients. In this study, we explored the role of OPN in GBM radioresistance using an OPN-depletion strategy in U87-MG, U87-MG vIII and U251-MG human GBM cell lines. Clonogenic experiments showed that OPN-depleted GBM cells were sensitized to irradiation. In comet assays, these cells displayed higher amounts of unrepaired DNA fragments post-irradiation when compared to control. We next evaluated the phosphorylation of key markers of DNA double-strand break repair pathway. Activating phosphorylation of H2AX, ATM and 53BP1 was significantly decreased in OPN-deficient cells. The addition of recombinant OPN prior to irradiation rescued phospho-H2AX foci formation thus establishing a new link between DNA repair and OPN expression in GBM cells. Finally, OPN knockdown improved mice survival and induced a significant reduction of heterotopic human GBM xenograft when combined with radiotherapy. This study reveals a new function of OPN in DNA damage repair process post-irradiation thus further confirming its major role in GBM aggressive disease.

Published
2016
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2. Eosinophilia predicts poor clinical outcomes in recent-onset arthritis: results from the ESPOIR cohort

Author

Dewi Guellec, Gabriel J. Tobón, Morgane Milin, Divi Cornec, Gilles Chiocchia, Alain Saraux, Valérie Devauchelle-Pensec, Olivier Vittecocq, Sandrine Jousse-Joulin, Thierry Marhadour, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Department of Internal Medicine (Dep Med - Div Rheum - CALI), Fundacion Vallee del Lili, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocyte B et Auto-immunité (LBAI), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
Pathology, MESH: Osteopontin, Inflammatory arthritis, [SDV]Life Sciences [q-bio], Arthritis, DMARDs (biologic), Early Arthritis, 0302 clinical medicine, Early Rheumatoid Arthritis, Immunology and Allergy, Medicine, Eosinophilia, MESH: Autoantibodies, 0303 health sciences, MESH: Arthritis, Rheumatoid, MESH: Peptides, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, respiratory system, MESH: Case-Control Studies, 3. Good health, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, Cohort, medicine.symptom, DMARDs (synthetic), Cohort study, medicine.medical_specialty, Visual analogue scale, Immunology, Rheumatoid Arthritis, 03 medical and health sciences, Rheumatology, Internal medicine, 030304 developmental biology, 030203 arthritis & rheumatology, MESH: Humans, business.industry, MESH: Alleles, MESH: Macrophages, MESH: Haplotypes, Eosinophil, medicine.disease, MESH: Male, business, MESH: Citrulline, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Objectives To determine the prevalence of eosinophilia in patients with recent-onset arthritis suggestive of rheumatoid arthritis (RA) and to describe their features and outcomes. Methods We performed an ancillary study of data from a French prospective multicentre cohort study monitoring clinical, laboratory and radiographic data in patients with inflammatory arthritis of 6 weeks to 6 months duration. We determined the proportion of patients with eosinophilia, defined as a count >500/mm3, at baseline and after 3 years. Features of patients with and without baseline eosinophilia were compared. Results Baseline eosinophilia was evidenced in 26 of 804 (3.2%) patients; their mean eosinophil count was 637.7±107/mm3. Baseline eosinophilia was ascribed to atopic syndrome in 6 of 26 (23.1%) patients. After 3 years, patients with eosinophilia had higher Health Assessment Questionnaire scores (0.9 vs 0.5, p=0.004), higher patient visual analogue scale activity score and morning stiffness intensity (p=0.05), and were more often taking disease-modifying antirheumatic drugs (p=0.02). Baseline eosinophilia was not associated with presence of extra-articular manifestations. Conclusions Eosinophilia is rare in recent-onset arthritis suggestive of RA, and is usually directly related to the rheumatic disease. Our data suggest that patients with mild eosinophilia at diagnosis could respond worse to the treatment than those without.

Published
2015
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3. SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis

Author

Gabriel J. Tobón, Thierry Schaeverbeke, Philippe Dieudé, Steven Gazal, Valérie Devauchelle-Pensec, Pierre-Antoine Juge, Hanna W. van Steenbergen, Bernard Combe, Arnaud Constantin, Annette H M van der Helm-van Mil, Delphine Nigon, Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of rheumatology, Leiden University Medical Center (LUMC), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Université Paris Diderot - Paris 7 (UPD7), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de rhumatologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Department of Rheumatology, Service de rhumatologie [Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique INSERM 1412 (CIC 1412 - BREST), Mécanismes, Conséquences et Modulation de l'Inflammation Ostéo-articulaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), and Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Male, Pathology, MESH: Osteopontin, [SDV]Life Sciences [q-bio], Arthritis, Rheumatoid, MESH: Genotype, 0302 clinical medicine, Early Rheumatoid Arthritis, Immunology and Allergy, MESH: Autoantibodies, MESH: Genetic Variation, MESH: Radiography, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Arthritis, Rheumatoid, MESH: Middle Aged, MESH: Genetic Predisposition to Disease, Middle Aged, Connective tissue disease, MESH: Case-Control Studies, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, Cohort, Disease Progression, Female, MESH: Disease Progression, Adult, musculoskeletal diseases, medicine.medical_specialty, MESH: Hand Joints, Genotype, Hand Joints, Immunology, Population, Rheumatoid Arthritis, Peptides, Cyclic, General Biochemistry, Genetics and Molecular Biology, MESH: Foot Joints, 03 medical and health sciences, Rheumatology, Gene Polymorphism, Internal medicine, Foot Joints, medicine, Humans, Genetic Predisposition to Disease, education, Genotyping, MESH: Peptides, Cyclic, 030304 developmental biology, Aged, Autoantibodies, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Autoantibody, Genetic Variation, MESH: Adult, medicine.disease, MESH: Male, Minor allele frequency, Radiography, Case-Control Studies, Ant-CCP, Osteopontin, Gene polymorphism, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Objective We recently reported an association of the SPP1 rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients. We hypothesised that SPP1 may contribute to the severity of joint destruction in RA, specifically in the ACPA-negative population. Methods Patients with RA in the ESPOIR cohort underwent genotyping for SPP1 rs9138 and rs11439060. Radiographs of the hands and feet were obtained at the first visit and at 1- and 2-year follow-up. Association analyses were performed by ACPA status. A replication study of the relevant subset of the Leiden Early Arthritis Clinic (EAC) cohort was performed. Results In the ESPOIR cohort (652 patients), rs9138 was significantly associated with radiological progression of joint destruction at 2 years, the association being restricted to 358 ACPA-negative patients (p=0.034). In the replication study with the Leiden EAC cohort (273 ACPA-negative patients), rs4754, which is in complete linkage disequilibrium with rs9138, was significantly associated with joint damage progression in ACPA-negative patients at 2- and 7-year follow-up (p=0.019 and p=0.005, respectively). Combined analysis of the two cohorts revealed a 0.95-fold rate of joint destruction per year per minor allele (p=0.022). Conclusions The SPP1 rs9138 variant contributes to joint damage progression in ACPA-negative RA.

Published
2014

4. Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum

Author

Patrick Lacolley, Daniel Henrion, Carlos Labat, Georges Leftheriotis, Anne Pizard, Y. Mauras, L. Martin, Gilles Kauffenstein, Theo G. M. F. Gorgels, Bertrand Toutain, E. Vessières, O. Le Saux, Linda Grimaud, Y. Le Corre, Arthur A.B. Bergen, Other departments, Amsterdam Neuroscience, Human Genetics, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Gériatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département de Pharmacologie-Toxicologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Hawai‘i [Mānoa] (UHM), MUMC+: AB Onderzoekers (9), Oogheelkunde, and RS: MHeNs - R3 - Neuroscience

Subjects
Male, MESH: Osteopontin, Messenger, Core Binding Factor Alpha 1 Subunit, MESH: Elastic Tissue, Gene mutation, Inbred C57BL, MESH: Mice, Knockout, MESH: Vascular Stiffness, calcification, Mice, Osteogenesis, MESH: SOXB1 Transcription Factors, MESH: Animals, Pseudoxanthoma Elasticum, MESH: Osteogenesis, MESH: Vascular Calcification, Mice, Knockout, physiologic, Arteries, MESH: Core Binding Factor Alpha 1 Subunit, Pseudoxanthoma elasticum, MESH: Gene Expression Regulation, 3. Good health, Arterial calcification, ABC transporters, MESH: Calcium, MESH: ATP-Binding Cassette Transporters, Biological Markers, MESH: Vasoconstriction, medicine.symptom, Multidrug Resistance-Associated Proteins, Cardiology and Cardiovascular Medicine, Chondrogenesis, MESH: Chondrogenesis, medicine.medical_specialty, MESH: Cell Transdifferentiation, Knockout, Myogenic contraction, MESH: Pseudoxanthoma Elasticum, MESH: Arterial Pressure, chemistry.chemical_element, Calcium, Biology, Article, Vascular Stiffness, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Mice, Inbred C57BL, Internal medicine, medicine, Animals, Arterial Pressure, RNA, Messenger, Vascular Calcification, Collagen Type II, MESH: Mice, MESH: Arteries, MESH: RNA, Messenger, arteriosclerosis, Animal, SOXB1 Transcription Factors, MESH: Collagen Type II, medicine.disease, Elastic Tissue, MESH: Male, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, chemistry, Gene Expression Regulation, Regional Blood Flow, Vasoconstriction, Disease Models, Cell Transdifferentiation, Arterial stiffness, MESH: Biomarkers, RNA, ATP-Binding Cassette Transporters, Osteopontin, MESH: Regional Blood Flow, MESH: Disease Models, Animal, Biomarkers, Calcification
Abstract

Objective— Pseudoxanthoma elasticum is an inherited metabolic disorder resulting from ABCC6 gene mutations. It is characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and the arterial wall. Despite calcium accumulation in the arteries of patients with pseudoxanthoma elasticum, functional consequences remain unknown. In the present study, we investigated arterial structure and function in Abcc6 −/− mice, a model of the human disease. Approach and Results— Arterial calcium accumulation was evaluated using alizarin red stain and atomic absorption spectrometry. Expression of genes involved in osteochondrogenic differentiation was measured by polymerase chain reaction. Elastic arterial properties were evaluated by carotid echotracking. Vascular reactivity was evaluated using wire and pressure myography and remodeling using histomorphometry. Arterial calcium accumulation was 1.5- to 2-fold higher in Abcc6 −/− than in wild-type mice. Calcium accumulated locally leading to punctuate pattern. Old Abcc6 −/− arteries expressed markers of both osteogenic (Runx2, osteopontin) and chondrogenic lineage (Sox9, type II collagen). Abcc6 −/− arteries displayed slight increase in arterial stiffness and vasoconstrictor tone in vitro tended to be higher in response to phenylephrine and thromboxane A2. Pressure-induced (myogenic) tone was significantly higher in Abcc6 −/− arteries than in wild type. Arterial blood pressure was not significantly changed in Abcc6 −/− , despite higher variability. Conclusions— Scattered arterial calcium depositions are probably a result of osteochondrogenic transdifferentiation of vascular cells. Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction evidenced in aged Abcc6 −/− mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis in the long term.

Published
2014
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5. Increased osteopontin expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient cells is associated with IL-17 expression

Author

Jean-Michel Mesnard, Raymond Césaire, Antoine Gross, Gildas Belrose, Sarkis Sarkis, Stéphane Olindo, Jean-Marie Peloponese, Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé (CPBS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie-Immunologie [Fort de France, Martinique] (EA 4537), Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Institut de Recherche en Infectiologie de Montpellier (IRIM), Service de neurologie [Fort-de-France, Martinique], and CHU de la Martinique [Fort de France]

Subjects
CD4-Positive T-Lymphocytes, Male, MESH: Paraparesis, Tropical Spastic, MESH: Osteopontin, medicine.medical_treatment, viruses, MESH: Interleukin-17, Pathogenesis, Myelopathy, 0302 clinical medicine, immune system diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, hemic and lymphatic diseases, Tropical spastic paraparesis, MESH: Gene Products, tax, Medicine, Osteopontin, Cells, Cultured, MESH: Aged, 0303 health sciences, Human T-lymphotropic virus 1, MESH: Middle Aged, biology, Interleukin-17, virus diseases, MESH: CD4-Positive T-Lymphocytes, Gene Products, tax, Middle Aged, Paraparesis, Tropical Spastic, 3. Good health, IL-17, Infectious Diseases, Cytokine, 030220 oncology & carcinogenesis, Carrier State, Female, Interleukin 17, MESH: Carrier State, MESH: Cells, Cultured, MESH: Asymptomatic Diseases, 03 medical and health sciences, MESH: Gene Expression Profiling, Virology, Humans, 030304 developmental biology, Aged, MESH: Human T-lymphotropic virus 1, MESH: Humans, business.industry, Gene Expression Profiling, medicine.disease, MESH: Male, Cell culture, HTLV-1, Immunology, Asymptomatic Diseases, biology.protein, business, HAM/TSP, Asymptomatic carrier, MESH: Female
Abstract

Background HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological inflammatory disease associated with a predominant infiltration of CD4+ T lymphocytes, which are the main subset of HTLV-1-infected cells. It has been demonstrated that in cell line the viral Tax protein transcriptionnally regulate expression of osteopontin, an inflammatory cytokine associated with Th17-related pathologies. Objectives The aim of the study was to explore osteopontin expression in HTLV-1 asymptomatic carriers and in HAM/TSP patients and consequences on IL17 expression. Study design We quantified Tax, osteopontin, RORγ, IL17 and IL22 mRNA expressions in cells from 10 HAM/TSP patients, 6 asymptomatic HTLV-1 carriers (ASY) and 4 HTLV-1-negative healthy donors during ex vivo culture. Results We observed that the expression of osteopontin was higher in HAM/TSP patients and correlated with Tax expression levels. Positive regulation of RORγ, IL17 and IL22 were also observed during cell culture. Conclusions Our results propose a new mechanism which could contribute to HAM/TSP pathogenesis.

Published
2012
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6. The Inflammatory Response in Acyl-CoA Oxidase 1 Deficiency (Pseudoneonatal Adrenoleukodystrophy)

Author

Pierre Andreoletti, Stéphane Mandard, Aurore Vluggens, Gérard Lizard, Sander Kersten, Janardan K. Reddy, H. I. El Hajj, Kévin Ragot, Ronald J.A. Wanders, H. R. Waterham, Mustapha Cherkaoui-Malki, Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire Bio-PeroxIL. Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique ( Bio-PeroxIL ), Université de Bourgogne ( UB ), Departments of Clinical Chemistry and Pediatrics, University of Amsterdam [Amsterdam] ( UvA ) -Academic Medical Centre, Nutrition, Metabolism and Genomics Group, Wageningen University and Research Centre [Wageningen] ( WUR ), Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ) -Universiteit van Amsterdam ( UvA ), Institut National de la Santé et de la Recherche Médicale, the Conseil Régional de Bourgogne, the Ministère de l'Enseignement Supérieur et de la Recherche, and the Centre National de la Recherche Scientifique., Mandard, Stéphane, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Laboratoire Bio-PeroxIL. Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique (Bio-PeroxIL), Université de Bourgogne (UB), University of Amsterdam [Amsterdam] (UvA)-Academic Medical Centre, Wageningen University and Research [Wageningen] (WUR), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), and University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Universiteit van Amsterdam (UvA)

Subjects
MESH: Inflammation, peroxisomal disorders, MESH: Osteopontin, medicine.medical_treatment, MESH : Immunohistochemistry, MESH : Transcriptome, chemokine receptors, Voeding, Metabolisme en Genomica, 0302 clinical medicine, Endocrinology, MESH: Reverse Transcriptase Polymerase Chain Reaction, Acyl-CoA oxidase, multiple-sclerosis lesions, MESH : Osteopontin, MESH : Fatty Acids, Cells, Cultured, Oligonucleotide Array Sequence Analysis, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Oxidase test, MESH : Gene Expression Regulation, Reverse Transcriptase Polymerase Chain Reaction, Fatty Acids, MESH: Acyl-CoA Oxidase, MESH : Reverse Transcriptase Polymerase Chain Reaction, Peroxisome, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Immunohistochemistry, MESH: Gene Expression Regulation, Metabolism and Genomics, 3. Good health, MESH: Fatty Acids, MESH : Oligonucleotide Array Sequence Analysis, Cytokine, Metabolisme en Genomica, ACOX1, Adrenoleukodystrophy, Nutrition, Metabolism and Genomics, MESH : Acyl-CoA Oxidase, medicine.symptom, Inflammation Mediators, MESH: Cells, Cultured, medicine.medical_specialty, MESH : Interleukin-8, MESH : Interleukin-6, MESH: Inflammation Mediators, Inflammation, Biology, in-vitro, MESH : Interleukin-1, MESH : Inflammation Mediators, 03 medical and health sciences, Voeding, Internal medicine, Peroxisomal disorder, nf-kappa-b, MESH : Cells, Cultured, MESH : Fibroblasts, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Nutrition, 030304 developmental biology, VLAG, MESH: Humans, MESH : Inflammation, Interleukin-6, MESH: Transcriptome, Interleukin-8, MESH : Humans, MESH: Interleukin-1, MESH: Immunohistochemistry, Fibroblasts, medicine.disease, MESH: Interleukin-6, MESH: Interleukin-8, Gene Expression Regulation, MESH: Fibroblasts, MESH: Oligonucleotide Array Sequence Analysis, cells, Brief Reports, Osteopontin, microarray analysis, Acyl-CoA Oxidase, Transcriptome, interleukin-1, 030217 neurology & neurosurgery, x-linked adrenoleukodystrophy, Interleukin-1
Abstract

Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids ( VLCFA) and inflammatory demyelination. However, the components of this inflammatory process in P-NALD remain elusive. In this study, we used transcriptomic profiling and PCR array analyses to explore inflammatory gene expression in patient fibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed to very-long-chain fatty acids exhibited increased mRNA expression of IL-1 alpha and IL-1 beta cytokines. Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated by MAPK, p38MAPK, and Jun N-terminal kinase inhibitors. Thus, the absence of acyl-coenzyme A oxidase 1 activity in P-NALD fibroblasts triggers an inflammatory process, in which the IL-1 pathway seems to be central. The use of specific kinase inhibitors may permit the modulation of the enhanced inflammatory status. (Endocrinology 153: 2568-2575, 2012)

Published
2012
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7. Osteopontin expression in cardiomyocytes induces dilated cardiomyopathy

Author

Patricia Reant, Fanny Robbesyn, Thierry Couffinhal, Flavien Charpentier, Karin Klingel, Danièle Daret, Claude Desgranges, Cécile Allières, Victorine Douin, Marie-Ange Renault, Isabelle Belloc, Pierre Dos Santos, Jean-François Arnal, Alain-Pierre Gadeau, Simon, Marie Francoise, Adaptation cardiovasculaire à l'ischemie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), 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), Department of Molecular Pathology, Institute for Pathology-Universitary Hospital of Tubingen, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiopathies et mort subite [ERL 3147], Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Heart disease, MESH: Osteopontin, Cardiomyopathy, MESH: Myocytes, Cardiac, 030204 cardiovascular system & hematology, Lymphocyte Activation, Mice, 0302 clinical medicine, Myocyte, Myocytes, Cardiac, MESH: Animals, Osteopontin, 0303 health sciences, biology, Dilated cardiomyopathy, 3. Good health, Myocarditis, Neutrophil Infiltration, MESH: Fibrosis, medicine.symptom, Cardiology and Cardiovascular Medicine, Cardiomyopathy, Dilated, medicine.medical_specialty, MESH: Mice, Transgenic, Mice, Transgenic, Inflammation, 03 medical and health sciences, stomatognathic system, MESH: Myocarditis, Internal medicine, medicine, Animals, MESH: Cardiomyopathy, Dilated, MESH: Lymphocyte Activation, MESH: Mice, 030304 developmental biology, Heart Failure, business.industry, medicine.disease, Fibrosis, Disease Models, Animal, MESH: Neutrophil Infiltration, Endocrinology, Heart failure, MESH: Heart Failure, biology.protein, MESH: Disease Models, Animal, business
Abstract

Background— Inflammatory processes play a critical role in myocarditis, dilated cardiomyopathy, and heart failure. The expression of the inflammatory chemokine osteopontin (OPN) is dramatically increased in cardiomyocytes and inflammatory cells during myocarditis and heart failure in human and animals. However, its role in the development of heart diseases is not known. Methods and Results— To understand whether OPN is involved in cardiomyopathies, we generated a transgenic mouse (MHC-OPN) that specifically overexpresses OPN in cardiomyocytes with cardiac-specific promoter-directed OPN expression. Young MHC-OPN mice were phenotypically indistinguishable from their control littermates, but most of them died prematurely with a half-life of 12 weeks of age. Electrocardiography revealed conduction defects. Echocardiography showed left ventricular dilation and systolic dysfunction. Histological analysis revealed cardiomyocyte loss, severe fibrosis, and inflammatory cell infiltration. Most of these inflammatory cells were activated T cells with Th1 polarization and cytotoxic activity. Autoantibodies against OPN, cardiac myosin, or troponin I, were not found in the serum of MHC-OPN mice. Conclusions— These data show that OPN expression in the heart induces in vivo T-cell recruitment and activation leading to chronic myocarditis, the consequence of which is myocyte destruction and hence, dilated cardiomyopathy. Thus, OPN might therefore constitute a potential therapeutic target to limit heart failure.

Published
2010
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8. Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity

Author

Adeline Bertola, Keith N. Frayn, Yannick Le Marchand-Brustel, Joan Tordjman, Moncef Dahman, S. McQuaid, Albert Tran, Philippe Gual, Karine Clément, Vanessa Deveaux, Jean Gugenheim, Pierre-Michel Huet, Rodolphe Anty, Déborah Rousseau, Sophie Lotersztajn, Abdelilah Wakkach, Stéphanie Bonnafous, Centre méditérannéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Signalisation moléculaire et obésité, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Transduction du Signal : Signalisation Calcique et Phosphorylation, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, physiopathologie et ingénierie du tissu osseux (GéPITOS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], Environnement et Grandes Cultures (EGC), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Service de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet II, Digestive Center, Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), 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), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -IFR50-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique, physiopathologie et ingénierie du tissu osseux ( GéPITOS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Oxford Centre for Diabetes, Endocrinology and Metabolism ( OCDEM ), Environnement et Grandes Cultures ( EGC ), AgroParisTech-Institut National de la Recherche Agronomique ( INRA ), Epidémiologie et écologie des maladies animales ( Epidémiologie ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ), CHU Nice, Université Nice Sophia Antipolis (1965 - 2019) (UNS), University of Oxford, and Service de Chirurgie Digestive / Centre de Transplantation Hépatique [CHU Nice]

Subjects
Male, MESH : RNA, Messenger, Endocrinology, Diabetes and Metabolism, Mice, 0302 clinical medicine, MESH : Oleic Acid, MESH: Animals, Osteopontin, MESH : Immunoblotting, MESH : Macrophages, Liver injury, 0303 health sciences, Tumor, MESH: Middle Aged, MESH: Immunoblotting, MESH : Reverse Transcriptase Polymerase Chain Reaction, Obesity, Morbid, Hyaluronan Receptors, Adipose Tissue, Tumor necrosis factor alpha, MESH: Adipose Tissue, medicine.medical_specialty, MESH: Gene Expression, MESH: Antigens, CD44, MESH : Adipose Tissue, 03 medical and health sciences, MESH: Weight Loss, Humans, MESH : Middle Aged, RNA, Messenger, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Humans, Tumor Necrosis Factor-alpha, Macrophages, MESH : Humans, MESH: Oleic Acid, MESH: Adult, medicine.disease, Mice, Inbred C57BL, MESH : Gene Expression, Endocrinology, MESH: Tumor Necrosis Factor-alpha, MESH: Female, MESH: Liver, MESH : Fatty Liver, MESH: Osteopontin, Messenger, Adipose tissue, Gene Expression, Inbred C57BL, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Antigens, CD44, MESH : Female, MESH : Osteopontin, CD44, Morbid, Receptor, MESH: Fatty Liver, MESH : Tumor Necrosis Factor-alpha, biology, Reverse Transcriptase Polymerase Chain Reaction, Fatty liver, MESH : Adult, Middle Aged, Liver, Female, Obesity Studies, Adult, MESH : Obesity, Morbid, MESH: Cell Line, Tumor, MESH : Male, Immunoblotting, 030209 endocrinology & metabolism, MESH : Mice, Inbred C57BL, Cell Line, Insulin resistance, stomatognathic system, MESH: Mice, Inbred C57BL, Cell Line, Tumor, Internal medicine, MESH : Mice, Weight Loss, Internal Medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, Antigens, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH : Cell Line, Tumor, MESH : Liver, MESH: Macrophages, MESH: Obesity, Morbid, MESH: Male, Fatty Liver, biology.protein, RNA, MESH : Animals, MESH : Weight Loss, Steatosis, Oleic Acid
Abstract

OBJECTIVE—Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis. RESEARCH DESIGN AND METHODS—OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells. RESULTS—Hepatic OPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery–induced weight loss induced a strong increase in circulating OPN. CONCLUSIONS—The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury.

Published
2009
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9. Preventive effects of nutritional doses of polyphenolic molecules on cardiac fibrosis associated with metabolic syndrome: involvement of osteopontin and oxidative stress

Author

Jacqueline Azay-Milhau, Gérard Cros, Pierre-Louis Teissedre, Thibault Sutra, E. Youl, Jean-Paul Cristol, R. Magous, Catherine Oiry, Centre de pharmacologie et innovation dans le diabète (CPID), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)

Subjects
Cardiac fibrosis, MESH: Osteopontin, MESH: Collagen Type I, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Resveratrol, medicine.disease_cause, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, MESH: Phenols, Fibrosis, MESH: Animals, Gallic acid, Osteopontin, chemistry.chemical_classification, 0303 health sciences, MESH: Oxidative Stress, biology, MESH: Heart Diseases, food and beverages, MESH: Reactive Oxygen Species, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, MESH: Insulin Resistance, MESH: Fibrosis, Delphinidin, General Agricultural and Biological Sciences, medicine.medical_specialty, Heart Diseases, MESH: Rats, Collagen Type I, 03 medical and health sciences, Phenols, Internal medicine, medicine, Animals, Humans, 030304 developmental biology, Flavonoids, Reactive oxygen species, MESH: Humans, Polyphenols, General Chemistry, medicine.disease, Rats, Oxidative Stress, Endocrinology, chemistry, biology.protein, Insulin Resistance, Reactive Oxygen Species, MESH: Flavonoids, Oxidative stress
Abstract

International audience; We previously showed that grape extracts enriched in different polyphenolic families were similarly able to prevent reactive oxygen species (ROS) production, although having differential effects on various features of metabolic syndrome when administered at a dose of 21 mg/kg to the fructose (60%)-fed rat (a model of metabolic syndrome). In the present work, we analyzed on the same model the effect of pure polyphenolic molecules (catechin, resveratrol, delphinidin, and gallic acid) administered at a dose of 2.1 mg/kg. Delphinidin and gallic acid prevented insulin resistance, while gallic acid prevented the elevation of blood pressure. All molecules prevented cardiac ROS overproduction and NADPH overexpression. We also showed that fructose feeding was associated with cardiac fibrosis (accumulation of collagen I) and expression of osteopontin, a factor induced by ROS and a collagen I expression inducer. Collagen I and osteopontin expressions were prevented by the administration of all polyphenolic molecules. The potential use of polyphenols in the prevention of cardiac fibrosis should be further explored.

Published
2008
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10. Dlx5 drives Runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme

Author

Martine Bontoux, Stéphanie Mateos, Karine Bollerot, Nicolas Holleville, Anne H. Monsoro-Burq, Laboratoire d'embryologie cellulaire et moléculaire (LECM), Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Régulations cellulaires et oncogenèse (RCO), Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Osteopontin, Cellular differentiation, [SDV]Life Sciences [q-bio], Core Binding Factor Alpha 1 Subunit, Chick Embryo, Mesoderm, 0302 clinical medicine, MESH: Alkaline Phosphatase, Runx2, Osteogenesis, MESH: Animals, MESH: Osteogenesis, Cells, Cultured, 0303 health sciences, MESH: Mesoderm, MESH: Cranial Sutures, FGF receptor, Cell Differentiation, MESH: Transcription Factors, DLX5, MESH: Chick Embryo, MESH: Core Binding Factor Alpha 1 Subunit, Cell biology, RUNX2, medicine.anatomical_structure, MESH: Antigens, Differentiation, Intramembranous ossification, embryonic structures, Primary calvaria cells, Bone differentiation, medicine.symptom, MESH: Cells, Cultured, musculoskeletal diseases, MESH: Cell Differentiation, medicine.medical_specialty, Mesenchyme, Calvaria, Biology, Transfection, 03 medical and health sciences, Internal medicine, MESH: Homeodomain Proteins, medicine, BMP, Animals, Dlx5, Molecular Biology, Endochondral ossification, 030304 developmental biology, Homeodomain Proteins, Ossification, Cell Biology, Cranial Sutures, Alkaline Phosphatase, Antigens, Differentiation, Endocrinology, Osteopontin, 030217 neurology & neurosurgery, Developmental Biology, Transcription Factors
Abstract

International audience; Craniofacial bones derive from cephalic neural crest, by endochondral or intramembranous ossification. Here, we address the role of the homeobox transcription factor Dlx5 during the initial steps of calvaria membranous differentiation and we show that Dlx5 elicits Runx2 induction and full osteoblast differentiation in embryonic suture mesenchyme grown "in vitro". First, we compare Dlx5 expression to bone-related gene expression in the developing skull and mandibular bones. We classify genes into three groups related to consecutive steps of ossification. Secondly, we study Dlx5 activity in osteoblast precursors, by transfecting Dlx5 into skull mesenchyme dissected prior to the onset of either Dlx5 and Runx2 expression or osteogenesis. We find that Dlx5 does not modify the proliferation rate or the expression of suture markers in the immature calvaria cells. Rather, Dlx5 initiates a complete osteogenic differentiation in these early primary cells, by triggering Runx2, osteopontin, alkaline phosphatase, and other gene expression according to the sequential temporal sequence observed during skull osteogenesis "in vivo". Thirdly, we show that BMP signaling activates Dlx5, Runx2, and alkaline phosphatase in those primary cultures and that a dominant-negative Dlx factor interferes with the ability of the BMP pathway to activate Runx2 expression. Together, these data suggest a pivotal role of Dlx5 and related Dlx factors in the onset of differentiation of chick calvaria osteoblasts.

Published
2006
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11. Paracrine and Autocrine Signals Promoting Full Chondrogenic Differentiation of a Mesoblastic Cell Line

Author

Michel Huerre, Odile Kellermann, Marie Boucquey, Huot Khun, Morgane Locker, Anne Poliard, Génétique moléculaire et intégration des fonctions cellulaires (GMIFC), Centre National de la Recherche Scientifique (CNRS), Brussels Branch and Cellular Genetics Unit, Ludwig Institute for Cancer Research, and Unité d'Anatomo-pathologie, Institut Pasteur

Subjects
MESH: Extracellular Matrix Proteins, MESH: Signal Transduction, MESH: Osteopontin, Endocrinology, Diabetes and Metabolism, Cellular differentiation, MESH: Bone Morphogenetic Proteins, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Insulin-Like Growth Factor I, MESH: Collagen Type I, SMAD, MESH: Triiodothyronine, Culture Media, Serum-Free, Dexamethasone, Mice, MESH: Transforming Growth Factor beta1, 0302 clinical medicine, MESH: Cell Aggregation, MESH: Aggrecans, Transforming Growth Factor beta, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Up-Regulation, Orthopedics and Sports Medicine, MESH: Animals, Aggrecans, Insulin-Like Growth Factor I, MESH: Sialoglycoproteins, BMP signaling pathway, Cell Aggregation, MESH: Collagen Type X, Extracellular Matrix Proteins, 0303 health sciences, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Reverse Transcriptase Polymerase Chain Reaction, High Mobility Group Proteins, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell Differentiation, SOX9 Transcription Factor, MESH: Gene Expression Regulation, Neoplastic, MESH: Transcription Factors, MESH: Culture Media, Serum-Free, Immunohistochemistry, Up-Regulation, Cell biology, Gene Expression Regulation, Neoplastic, Autocrine Communication, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Dexamethasone, MESH: Proteoglycans, Bone Morphogenetic Proteins, Triiodothyronine, MESH: Pluripotent Stem Cells, Proteoglycans, Signal Transduction, Pluripotent Stem Cells, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Cell Line, Tumor, Sialoglycoproteins, Biology, Bone morphogenetic protein, MESH: Bone Morphogenetic Protein Receptors, Collagen Type I, Chondrocyte, Transforming Growth Factor beta1, 03 medical and health sciences, Paracrine signalling, MESH: SOX9 Transcription Factor, Chondrocytes, Cell Line, Tumor, Internal medicine, MESH: Chondrocytes, Paracrine Communication, MESH: Receptors, Growth Factor, medicine, Animals, MESH: Blotting, Northern, Lectins, C-Type, Receptors, Growth Factor, MESH: Paracrine Communication, Autocrine signalling, Collagen Type II, MESH: Mice, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Immunohistochemistry, Bone Morphogenetic Protein Receptors, MESH: Collagen Type II, Blotting, Northern, Chondrogenesis, MESH: High Mobility Group Proteins, Endocrinology, Osteopontin, MESH: Autocrine Communication, MESH: Lectins, C-Type, Collagen Type X, Transcription Factors
Abstract

The pluripotent mesoblastic C1 cell line was used under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to drive chondrogenesis. Sequential addition of two systemic hormones, dexamethasone and triiodothyronine, permits full chondrogenic differentiation. The cell intrinsic activation of the BMP signaling pathway and Sox9 expression occurring on mesoblastic condensation is insufficient for recruitment of the progenitors. Dexamethasone-dependent Sox9 upregulation is essential for chondrogenesis. Introduction: Differentiation of lineage stem cells relies on cell autonomous regulations modulated by external signals. We used the pluripotent mesoblastic C1 cell line under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to induce differentiation of a precursor clone along the chondrogenic lineage. Materials and Methods: C1 cells, cultured as aggregates, were induced toward chondrogenesis by addition of 10−7 M dexamethasone in serum-free medium. After 30 days, dexamethasone was replaced by 10 nM triiodothyronine to promote final hypertrophic conversion. Mature and hypertrophic phenotypes were characterized by immunocytochemistry using specific antibodies against types II and X collagens, respectively. Type II collagen, bone morphogenetic proteins (BMPs), BMP receptors, Smads, and Sox9 expression were monitored by reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot, and/or Western blot analysis. Results and Conclusions: Once C1 cells have formed nodules, sequential addition of two systemic hormones is sufficient to promote full chondrogenic differentiation. In response to dexamethasone, nearly 100% of the C1 precursors engage in chondrogenesis and convert within 30 days into mature chondrocytes, which triggers a typical cartilage matrix. On day 25, a switch in type II procollagen mRNA splicing acted as a limiting step in the acquisition of the mature chondrocyte phenotype. On day 30, substitution of dexamethasone with triiodothyronine triggers the final differentiation into hypertrophic chondrocytes within a further 15 days. The chondrogenic process is supported by intrinsic expression of Sox9 and BMP family genes. Similarly to the in vivo situation, activation of Sox9 expression and the BMP signaling pathway occurred on mesoblastic condensation. After induction, BMP-activated Smad nuclear translocation persisted throughout the process until the onset of hypertrophy. After dexamethasone addition, Sox9 expression was upregulated. Dexamethasone withdrawal reversed the increase in Sox9 expression and stopped differentiation. Thus, Sox9 seems to be a downstream mediator of dexamethasone action.

Published
2004
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