基于Sox9基因逆分化肥大软骨细胞对骨性关节炎的治疗及其作用机制研究

Osteoarthritis, in a large extent, is mediated by the terminal differentiation (hypertrophy) of the articular chondrocytes, which do not experience this abnormal process under normal circumstances. Accordingly, if this terminal differentiation was suppressed or even reversed by some methods, the chondrocytes will be deliberately locked at the undifferentiated status, then the occurrence and progression of this disease can be blocked at an early stage. Our previous studies revealed that Sox9 gene over-expression promoted degenerated chondrocytes retrieve normal phenotype, increased the production of extracellular matrix and inhibited WNT pathway related proteins. This project is mainly talked about the critical issue of "how to intervene and treat osteoarthritis at an early period"; based on the Sox9 gene, several important issues are further investigated, "whether Sox9 gene over-expression could inhibit osteoarthritis chondrocytes hypertrophy in vivo", "how does Sox9 gene regulate chondrocyte hypertrophy, its molecular mechanism and its target gene in the Wnt pathway", "whether regulation of Sox9 and Wnt pathway simultaneously is more effective for the treatment of osteoarthritis". Expected results will benefit not only for the understanding of the molecular mechanisms of osteoarthritis, but also for the providing of new ideas and targets for the treatment of osteoarthritis.

骨关节炎在很大程度是由原本处于分化阻滞状态的关节软骨细胞发生终末分化（肥大化）所介导的。因此，如果能够通过某种手段抑制,甚至逆转软骨细胞终末分化，那么软骨细胞将被特意锁定于未分化阶段，从而在早期即阻断骨关节炎的疾病发生和进展。前期研究证实Sox9基因过表达促进退变软骨细胞基质分泌，同时抑制WNT通路信号蛋白的表达。因此本项目紧紧抓住"如何早期干预、早期治疗骨关节炎"这一关键问题不放，拟以Sox9基因为切入点，深入研究"Sox9于体内是否能够抑制骨关节炎软骨细胞肥大化"、"Sox9以Wnt通路中哪个信号分子为靶点来调控软骨细胞肥大化及其分子机制"和"同时调控Sox9和Wnt通路是否对骨关节炎的治疗更有效"等重要问题。本研究不仅能为骨关节炎发病分子机制的研究提供更丰富、深入的资料，更重要地，为骨关节炎的细胞与基因治疗做出有益尝试。