Recherche de liens entre expression d'ARN non codants et physiopathologies articulaires, utilisation des microARN comme biomarqueurs du phénotype chondrocytaire

Abstract : Osteoarthritis (OA) is the most frequent joint disease and its prevalence still grows with the increase in lifespan. OA is characterized by articular cartilage degeneration, together with synovitis and abnormal subchondral bone remodeling, leading to progressive loss of mobility and pain. Chondrocyte is the unique cell type in cartilage which accounts for the synthesis of extracellular matrix (ECM) components (collagens, proteoglycans). During OA, chondrocyte phenotype is altered and the balance between ECM synthesis and degradation is impaired towards cartilage degradation. To date no treatment can efficiently reduce OA progression so that the search for reliable biomarkers and potential therapeutic targets is very active, particularly since the discovery of microRNAs. miRNAs are estimated to regulate 50% of cellular genes. They contribute to major cellular processes such as cell differentiation, apoptosis or tumorigenesis. Therefore, miRNAs are interesting putative biomarkers. During this PhD thesis, we studied the contribution of miARNs to the control of chondrocyte phenotype. Using a model of chondrocyte differentiated phenotype loss induced by extensive subculturing or IL-1[beta] challenge we studied changes in miRNAs profile with microarrays. We determined a panel of 43 varying miRNA including the miR-23~27b~24-1 cluster and miR-29b. The differential production of miRNAs from this cluster has been investigated, but we didn’t succeed in identifying the underlying mechanisms. However, we identified miR-29b as a negative post-transcriptional regulator of Col-IIa1 during differentiated phenotype loss and OA. Finally, as equilibrium between extracellular levels of inorganic phosphate and pyrophosphate (ePi/ePPi) was previously shown in the laboratory to be crucial for the maintenance of a differentiated chondrocyte phenotype, we studied the regulation of the genes encoding the 4 proteins regulating this balance (ANK, PC1, Pit-1 and TNAP). From in silico analysis, we selected a panel of 4 miRNAs: let7e, miR-9, miR-188 and miR-219. Using reporter assays, we showed that miR-9 was a negative regulator of PC-1, Pit-1 and TNAP, according or not to bioinformatics prediction
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Thomas Clément. Recherche de liens entre expression d'ARN non codants et physiopathologies articulaires, utilisation des microARN comme biomarqueurs du phénotype chondrocytaire. Médecine humaine et pathologie. Université de Lorraine, 2014. Français. ⟨NNT : 2014LORR0113⟩. ⟨tel-01750898⟩

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