Abstract
Dysregulation of Wnt signaling has been implicated in developmental defects and in the pathogenesis of many diseases such as osteoarthritis; however, the underlying mechanisms are poorly understood. Here, we report that non-canonical Wnt signaling induced loss of chondrocyte phenotype through activation of Fz-6/DVL-2/SYND4/CaMKIIα/B-raf/ERK1/2 cascade. We show that in response to Wnt-3a, Frizzled 6 (Fz-6) triggers the docking of CaMKIIα to syndecan 4 (SYND4) and that of B-raf to DVL-2, leading to the phosphorylation of B-raf by CaMKIIα and activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling, which leads to chondrocyte de-differentiation. We demonstrate that CaMKIIα associates and phosphorylates B-raf in vitro and in vivo. Our study reveals the mechanism by which non-canonical Wnt activates ERK1/2 signaling that induces loss of chondrocyte phenotype, and demonstrates a direct functional relationship between CaMKIIα and B-raf during chondrocyte de-differentiation. The identification of Fz-6, SYND4, and B-raf as novel physiological regulators of chondrocyte phenotype may provide new potential anti-osteoarthritic targets.
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This work was supported by Agence Nationale de la Recherche (ANR: Solv-CDG) and by Région Lorraine.
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Xie, Z., Khair, M., Shaukat, I. et al. Non-canonical Wnt induces chondrocyte de-differentiation through Frizzled 6 and DVL-2/B-raf/CaMKIIα/syndecan 4 axis. Cell Death Differ 25, 1442–1456 (2018). https://doi.org/10.1038/s41418-017-0050-y
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DOI: https://doi.org/10.1038/s41418-017-0050-y
