WNT10A通过介导HDAC5磷酸化对骨关节炎中衰老滑膜干细胞的清除作用及机制研究

申请人在前期研究中发现骨关节炎（OA）中存在的大量“衰老”滑膜残留间充质干细胞（SMSCs）是加重OA进展的关键病理机制之一。探索如何清除这些衰老SMSCs对于OA的治疗具有重要意义。通过对临床样本的检测和体外预实验，申请人发现WNT10A能够特异性地诱导体外衰老SMSCs的凋亡。已知WNT10A下游的CaMKII能够介导HDAC5的胞质转位，又知HDAC5的胞质转位可能抑制p53/p21Cip1通路，而p21Cip1的抑制可以诱导衰老细胞凋亡。因此申请人假设：WNT10A通过CaMKII-HDAC5-p21Cip1通路诱导凋亡是一种清除衰老SMSCs的重要机制，具有可观的临床潜力和研究价值。本项目拟探索该机制，并评估关键分子靶点的干预对OA的治疗效果。本项目的完成将为OA的治疗开拓一条新的策略。

In the previous study, the applicant found that the "senescent" synovial residual mesenchymal stem cells (SMSCs) in osteoarthritis (OA) is one of the key pathological mechanisms that aggravate the progression of OA. Exploring how to eliminate these senescent SMSCs is of great significance for the treatment of OA. Through the detection of clinical samples and in vitro pre-test, the applicant found that WNT10A can specifically induce the apoptosis of in vitro senescent SMSCs. It is known that CaMKII, downstream of WNT10A, could mediate HDAC5 nuclear export, and HDAC5 nuclear export could result in p53/p21Cip1 pathway inhibition, which could subsequently promote apoptosis of senescent cells. Therefore, we hypothesized that WNT10A induced apoptosis through CaMKII-HDAC5-p21Cip1 pathway is an important mechanism for the clearance of senescent SMSCs. This project intends to demonstrate this mechanism, and to evaluate the therapeutic effect of key molecular targets intervention on OA development. The completion of this project will develop a new strategy for the treatment of OA.