Sfrp4通过抑制Wnt通路调控关节软骨及软骨下骨发挥抗骨关节炎作用的机制研究

临床上迫切需要可以逆转骨关节炎（OA）病理过程的药物。Wnt信号通路与OA病情进展密切相关，以Wnt通路抑制剂为靶点寻找治疗OA的药物是当前研究的热点。分泌型卷曲蛋白4（Sfrp4）可以与Wnt蛋白直接结合，从而抑制Wnt通路。申请人首次发现Sfrp4可以通过抑制Ror2/Jnk非经典Wnt通路抑制破骨细胞骨吸收，调控皮质骨厚度。但是，Sfrp4与OA治疗的关系，迄今国内外尚无报道。预实验结果显示，OA软骨中Sfrp4表达量明显降低。同时，Sfrp4可以缓解IL-1β引起的软骨细胞凋亡和基质降解，减少OA软骨下骨的骨量流失。且Sfrp4能够抑制软骨细胞中的Wnt通路。据此我们推测，Sfrp4可以通过抑制Wnt信号通路调控关节软骨与软骨下骨，从而发挥抗OA作用。本课题拟在分子、细胞、动物整体水平阐明Sfrp4蛋白在OA治疗中的作用及其分子机制。项目的成功实施将为OA治疗提供新的思路和方法。

There is an urgent need for disease-modifying osteoarthritis (OA) drug in clinic. Considering that Wnt signaling is closely related to the progression of OA, Wnt inhibitors have become one of the promising new targets for treating OA. Secreted Frizzled Related Protein 4 (Sfrp4) is known as a kind of Wnt inhibitors that could bind directly to the Wnt ligands and inhibit Wnt signaling pathway. Our previous work has shown that Sfrp4 repression of the Ror2/Jnk non-canonical Wnt signaling could inhibit osteoclast bone resorption function and ensure normal cortical bone thickness. However, the function of Sfrp4 in OA treatment remains unknown. Our preliminary data suggested that the expression of Sfrp4 decreased dramatically in OA chondrocytes. Meanwhile, Sfrp4 could alleviate IL-1β induced chondrocytes apoptosis ,reduce cartilage degradation and decrease the bone loss of OA subchondral bone. Moreover, Sfrp4 inhibited Wnt signaling in OA chondrocytes according to our preliminary experiments. Hereby, our hypothesis is that:” Sfrp4 repression of the Wnt signaling alleviates OA via targeting articular chondrocytes and subchondral bone”. Our project aims to explore the role of Sfrp4 in OA treatment. And the successful implementation of this project will produce new breakthroughs in the treatment of OA.