Régulation de la synthèse des protéoglycanes et du phénotype chondrocytaire par l'interleukine 1 et Wnt-3a : rôle clé de la xylosyltransférase I et du syndécan 4

Abstract : Osteoarthritis is characterized by progressive degeneration of articular cartilage. It is characterized by the increase in pro-inflammatory cytokines, in particular interleukin 1ß (IL- 1ß ) which inhibits the synthesis of proteoglycans (PGs ) and increases their degradation leading to erosion of cartilage. However, the molecular mechanism of this inhibition is not yet elucidated. We studied the effect of IL-1ß on gene expression of the xylosyltransferase I ( XT- I), an enzyme which plays an essential role in regulating the synthesis of PGs in the cartilage. We showed that IL-1ß regulates the expression of the XT-I gene into two phases: an early phase of induction and a late phase of inhibition. The study of the regulation of the promoter of the human XT-I gene showed that the early induction phase by IL-1ß is mediated by AP-1 while the late inhibition phase involves the Sp3 transcription factor. We also investigated the molecular mechanisms involved in the inhibition of PG anabolism and induction of chondrocyte dedifferentiation by Wnt-3a. We showed that Wnt-3a inhibits expression of the PG syndecan 4 in human cartilage and in cultured chondrocytes via the non-canonical signaling pathway involving the kinase ERK1/2. We also showed that inhibition of the expression of collagen II by Wnt-3a is mediated by syndecan 4, probably via interaction with a regulatory protein Dishevelled and that syndecan 4 is essential for non-canonical Wnt pathway signaling. Finally, we demonstrated that the deleterious effects of IL-1ß on PGs and collagen II are reduced by Wnt-3a by inhibiting the expression of ADMTS4 and MMP13
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Mostafa Khair. Régulation de la synthèse des protéoglycanes et du phénotype chondrocytaire par l'interleukine 1 et Wnt-3a : rôle clé de la xylosyltransférase I et du syndécan 4. Biochimie, Biologie Moléculaire. Université de Lorraine, 2014. Français. ⟨NNT : 2014LORR0005⟩. ⟨tel-01750666⟩

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