骨关节炎(OA)是临床上最常见的一种关节炎，主要病理特征是滑膜增生、关节软骨破坏和骨赘形成。OA发病机制未明，尚无有效治疗方法。我们预实验发现：OA患者关节组织中miR-204/-211表达降低；而且间充质干细胞（MSC）特异性miR-204/-211双敲除小鼠出现典型的OA表型，尤其是滑膜增生明显。结合文献miR-204/-211在体外能够抑制正常MSC中Runx2的表达，我们推测“miR-204/-211靶标Runx2，抑制滑膜增生和软骨破坏，进而抑制OA发生发展”。本项目拟采用病毒感染、RNA干扰、基因芯片、细胞特异性基因敲除、OA小鼠模型、OA患者标本等，从分子、细胞、组织和整体水平验证该假说，揭示Runx2促进滑膜增生和滑膜炎症参与OA发病的机制，明确miR-204/-211的靶基因和抑制OA发生发展的具体信号传导通路，为miR-204/-211治疗OA和研制抗OA新药提供依据。

Osteoarthritis (OA) is the most common form of arthritis, with the pathological characteristics of synovial hyperplasia, articular cartilage degradation, subchondral sclerosis, and osteophyte formation. The pathological mechanisms of OA are currently unknown and no effective therapeutic intervention is available to decelerate the OA progression. Our preliminary studies demonstrated that the expression of miR-204/-211 in joint tissues was significantly decreased in patients with OA. We then generated limb mesenchymal cell-specific miR-204/-211 double knockout (dKO) mice to investigate the role of miR-204/-211 in joint tissue homeostasis in vivo. Several typical OA features were observed in these dKO mice, especially the severe synovial hyperplasia. Combined with the in vitro findings reported in the literature that miR-204/-211 negatively regulate Runx2 expression in mesenchymal stem cells (MSC), we hypothesize that miR-204/-211 inhibits synovial hyperplasia and cartilage destruction through down-regulation of Runx2 expression, thereby inhibiting the initiation and progression of OA. In the proposed studies, we intend to use viral infection, RNA interference, gene chip, cell-specific conditional KO mice, animal model of OA, and knee joint specimens derived from OA patients, to test our hypothesis at molecular, cellular, and tissue levels using in vitro and in vivo approaches. Through proposed studies we will reveal the mechanism by which up-regulation of Runx2 leads to synovial hyperplasia and synovial inflammation during OA development. We will also define the specific signaling pathway of miR-204/-211-Runx2 network in joint tissues. Our studies will provide novel insights into the role of miR-204/-211 as potential agents in the treatment of OA disease.