Gli1+软骨表层细胞Rac1/NF-kB/MIP-1α通路在骨性关节炎发生中的作用及机制研究

骨性关节炎（OA）是以关节软骨退变为主要病理表现的炎症性疾病，与关节异常力学载荷高度相关，但异常力学载荷引起关节炎症的机制不明。申请人发现，软骨表层细胞（SFC）代谢紊乱是OA发生的极早期改变；异常载荷下SFC代谢紊乱可促进关节内巨噬细胞募集，且通过NF-kB通路激活巨噬细胞炎性蛋白1α（MIP-1α）的高表达。研究报道，Rac1是将力学信号转换为生物学功能的重要蛋白，处于NF-kB通路上游。综上推测：异常力学载荷通过上调SFC的Rac1/NF-kB/MIP-1α通路，募集巨噬细胞，引起关节炎症与OA发生发展。本项目拟首先在OA不同阶段检测SFC的Rac1/NF-kB/MIP-1α通路和关节炎症变化；进而明确SFC的Rac1通路引起巨噬细胞募集与关节炎症的作用；最后阐明SFC的Rac1通路介导异常力学载荷所致巨噬细胞募集并引起关节炎症和OA发生的机制。项目的开展可为OA早期治疗提供新思路。

Osteoarthritis (OA) is a joint inflammatory disease mainly characterized by cartilage degeneration, and is highly associated with abnormal mechanical loading on the joints. The mechanism of local inflammation caused by abnormal mechanical loading is not well delineated. We found that the metabolic disorder of cartilage superficial layer cells (SFC) is a very early sign of OA; metabolic disorder of SFC could promote macrophage recruitment, which is modulated by MIP-1α secretion of SFC via upregulated NF-kB signaling pathway. It is reported that Rac1 protein, in the upstream of the NF-kB pathway, is an important mechanotransduction protein that convert mechanical signals to biological functions. Therefore, it was speculated that the Rac1/NF-kB/MIP-1α pathway of SFC was abnormally activated by abnormal mechanical loading and could recruit macrophages, thus leading to joint inflammation and then OA progression. Firstly, we aim to study the Rac1/NF-kB/MIP-1α pathway level of SFC and progression of joint inflammation, to investigate the correlation of Rac1/NF-kB/MIP-1α pathway, macrophages infiltration and joint inflammation. Next, we will demonstrate how Rac1/NF-kB/MIP-1α mediates macrophage recruitment and OA progression by abnormal mechanical loading. This study could help provide new therapeutic target of OA treatment.