UMR7365 CNRS-University of Lorraine, Biopôle, Faculty of Medicine, 54505, Vandoeuvre-lès-Nancy, France.
Cell Death Differ. 2018 Aug;25(8):1442-1456. doi: 10.1038/s41418-017-0050-y. Epub 2018 Jan 19.
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.
Wnt 信号通路失调与发育缺陷以及许多疾病的发病机制有关，如骨关节炎；然而，其潜在的机制仍不清楚。在这里，我们报告非经典 Wnt 信号通过激活 Fz-6/DVL-2/SYND4/CaMKIIα/B-raf/ERK1/2 级联反应导致软骨细胞表型丧失。我们表明，在响应 Wnt-3a 时，Frizzled 6 (Fz-6) 触发 CaMKIIα 与 syndecan 4 (SYND4) 的对接，以及 B-raf 与 DVL-2 的对接，导致 CaMKIIα 对 B-raf 的磷酸化和细胞外信号调节激酶 1 和 2 (ERK1/2) 信号的激活，导致软骨细胞去分化。我们证明 CaMKIIα 在体外和体内与 B-raf 结合并磷酸化 B-raf。我们的研究揭示了非经典 Wnt 激活 ERK1/2 信号诱导软骨细胞表型丧失的机制，并证明了 CaMKIIα 和 B-raf 在软骨细胞去分化过程中的直接功能关系。Fz-6、SYND4 和 B-raf 作为软骨细胞表型的新的生理调节剂的鉴定可能为新的抗骨关节炎靶点提供了依据。
