骨关节炎（OA）是导致关节疼痛、引起致残的首位关节疾病，发病机制不明且缺乏有效的疾病干预性药物。最新研究证实软骨细胞衰老与OA发生、发展密切相关。FoxO及miR-17-92 cluster是调控骨软骨发育及细胞周期的一类重要转录因子与功能性非编码RNA，申请人前期研究发现OA小鼠软骨组织中FoxO、miR-17-92表达下调，p16表达上调，且存在相关性。进一步研究发现软骨细胞条件性敲除miR-17-92后的成年鼠表现出：软骨退变加重，衰老软骨细胞及p16表达增多。申请人设想miR-17-92与上游转录因子FoxO及下游p16组成的信号轴可精准调控软骨细胞衰老与OA的发生发展过程。拟分别从临床、动物、细胞三个层面研究FoxO/ miR-17-92 cluster/ p16信号轴在调控软骨细胞衰老及OA发生发展中的作用及机制，为OA疾病干预性药物的开发提供新的思路与靶点。

Osteoarthritis (OA) is the most common joint disease that causes pain and disability. Its pathogenesis is unknown and there is a lack of disease-modifying drugs in clinic. Recent studies have confirmed that chondrocyte senescence is closely related to the onset and progression of OA. FoxO and miR-17-92 cluster are important transcription factors and functional non-coding RNA regulating osteochondral development and cell cycle. Our preliminary studies show that the expression of FoxO and miR-17-92 were down-regulated in OA cartilage of wild-type mice, while p16 unregulated, and there was correlation between them. Meanwhile, conditional knock out of miR-17-92 cluster in chondrocytes results in more serious cartilage degeneration, more senescent chondrocytes, and higher level of p16. These data indicated that the signal axis composed of miR-17-92, upstream transcription factor FoxO and downstream p16 could precisely regulate the senescence of chondrocyte and the onset and progression of OA. The purpose of this study is to investigate the role and mechanism of FoxO/miR-17-92 cluster/p16 axis in the regulation of chondrocyte senescence and the development of OA from clinical, vivo and vitro experiment, so as to provide new ideas and targets for the diagnosis and treatment of OA.