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Wnt signaling in human cartilage degeneration and chondrocytes de-differentiation

Abstract : Dysregulation of Wnt signaling has been implicated in developmental defects and in the pathogenesis of many diseases, including osteoarthritis. Here, we studied the effect of Wnt-3a on ADAMTS-4 in human cartilage explants and primary chondrocytes and found that Wnt-3a negatively regulates the expression of this aggrecanase. We demonstrated that Wnt-3a inhibition of ADAMTS-4 expression is mediated by Frizzled-8 through activation of the canonical Wnt/ß-catenin pathway leading to inhibition of NFκB activity and down-regulation of ADAMTS-4. Furthermore, we showed that Wnt-3a is able to counteract the induction of ADAMTS-4 by IL-1ß, therefore indicating that Wnt/ß-catenin pathway may play a protective role in osteoarthritis. On the other hand, Non-canonical Wnt signaling induces loss of phenotypic stability of articular chondrocytes which represents an early event in osteoarthritis, but the underlying mechanisms are poorly understood. In this thesis, we identify Wnt/CaMKII/B-raf/ERK1/2 cascade as non-canonical signaling pathway that modulates chondrocyte phenotype and revealed that syndecan4 is an essential component of this pathway. We show that in response to Wnt-3a, Fz-6 activates non-canonical signaling by triggering the docking of CaMKIIα to syndecan4 and that of B-raf to DVL-2 leading to the activation of B-raf that transduces signals to ERK1/2 MAPK. In a feedback loop, non-canonical Wnt down-regulates the expression of syndecan4 to negatively regulate the signaling. Our finding uncovers a previously unanticipated role of syndecan4 as a regulator of chondrocyte differentiation. This study also provides new targets which may have therapeutic potential in osteoarthritis
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https://hal.univ-lorraine.fr/tel-01752343
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Zhe Xie. Wnt signaling in human cartilage degeneration and chondrocytes de-differentiation. Rhumatology and musculoskeletal system. Université de Lorraine, 2016. English. ⟨NNT : 2016LORR0111⟩. ⟨tel-01752343⟩

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