TGFβ-ACVR1/BMPR1A-P16轴诱导骨关节炎干细胞衰老促进骨关节炎形成的机制研究

越来越多的研究证实软骨组织中存在不只一类细胞，但极少有研究将多种细胞分开研究。申请人前期研究明确阐释了TGFβ对骨关节炎软骨组织中软骨细胞及干细胞存在相反的调控机制。因此，将两类细胞合并研究会导致结果的不准确。骨关节炎与细胞衰老密切相关，杀死P16（衰老相关基因）阳性细胞可抑制骨关节炎，而敲除软骨细胞中P16基因并不会改变骨关节炎的进程。申请人研究发现位于骨关节软骨组织内的骨关节炎干细胞是一类衰老细胞，其高表达P16并分泌大量炎症因子，显著高于骨关节炎软骨细胞。另外，骨关节炎干细胞中存在TGFβ信号的异常激活，能够通过与ACVR1/BMPR1A结合激活下游信号进而诱发骨关节炎。本项目拟在此工作基础上，证实骨关节炎干细胞及其P16基因的表达是诱发骨关节炎的关键，而激活此通路需要借由骨关节炎干细胞中TGFβ-ACVR1/BMPR1A异常响应途径完成。这为骨关节治疗提供了全新的靶细胞与靶分子。

Recently, although more and more evidences proved that chondrocyte was not the only type of cell in cartilage, rare studies investigated the different types of cells in cartilage separately. We clarified that the different mechanism of TGFβ response in chondrocyte and osteoarthritis stem cell located in osteoarthritis cartilage. Moreover, the function of TGFβ in the two types of cells was totally opposite. Therefore, investigating the cells combined would bring some inaccurate results. Osteoarthritis was related with cell senescence according lots of literatures. Deletion of P16 positive cells could attenuate osteoarthritis. However, deletion of P16 in chondrocyte could not prevent the process of osteoarthritis. We proved that osteoarthritis stem cells were senescence cells in osteoarthritis cartilage, which was with higher level of P16 expression and inflammation than chondrocyte. In addition, there was the lateral signaling activation in osteoarthritis stem cell. That is, TGFβ could bind ACVR1/BMPR1A to active downstream signals and contribute to osteoarthritis progression. This project plans to clarify that the osteoarthritis and its P16 expression are the key factors of osteoarthritis formation. The lateral signaling TGFβ-ACVR1/BMPR1A-P16 in osteoarthritis stem cell is the underlying mechanism, which provide the target cell and target gene for osteoarthritis therapy.