Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Sci Adv. 2023 Aug 4;9(31):eadf1130. doi: 10.1126/sciadv.adf1130.
In osteoarthritis (OA), a disease characterized by progressive articular cartilage degradation and calcification, the articular chondrocyte phenotype changes and this correlates with actin cytoskeleton alterations suggesting that it regulates gene expression essential for proper phenotype. This study reports that OA is associated with the loss of adseverin, an actin capping and severing protein. Adseverin deletion (Adseverin) in mice compromised articular chondrocyte function, by reducing F-actin and aggrecan expression and increasing apoptosis, Indian hedgehog, Runx2, MMP13, and collagen type X expression, and cell proliferation. This led to stiffer cartilage and decreased hyaline and increased calcified cartilage thickness. Together, these changes predisposed the articular cartilage to enhanced OA severity in Adseverin mice who underwent surgical induction of OA. Adseverin chondrocyte RNA sequencing and in vitro studies together suggests that adseverin modulates cell viability and prevents mineralization. Thus, adseverin maintains articular chondrocyte phenotype and cartilage tissue homeostasis by preventing progression to hypertrophic differentiation in vivo. Adseverin may be chondroprotective and a potential therapeutic target.
在骨关节炎（OA）中，一种以进行性关节软骨降解和钙化为特征的疾病，关节软骨细胞表型发生变化，这与肌动蛋白细胞骨架的改变相关，表明其调节对适当表型至关重要的基因表达。本研究报告 OA 与衔接蛋白（adseverin）的缺失相关，衔接蛋白是一种肌动蛋白盖帽和切割蛋白。在小鼠中敲除衔接蛋白（Adseverin）会降低 F-actin 和聚集蛋白的表达，增加细胞凋亡、印度刺猬因子、Runx2、MMP13 和胶原 X 的表达，从而损害关节软骨细胞的功能，增加细胞增殖。这导致软骨更硬，透明软骨和钙化软骨的厚度减少。这些变化使关节软骨更容易发生骨关节炎，在接受骨关节炎手术诱导的 Adseverin 小鼠中，骨关节炎的严重程度增加。衔接蛋白软骨细胞 RNA 测序和体外研究表明，衔接蛋白调节细胞活力并防止矿化。因此，衔接蛋白通过防止体内向肥大分化来维持关节软骨细胞表型和软骨组织的稳态。衔接蛋白可能具有软骨保护作用，是一种潜在的治疗靶点。
