GAS6/Axl促进成纤维样滑膜细胞增殖在OA滑膜增生中的作用及调控机制研究

Emerging evidence suggests that fibroblast-like synoviocytes (FLSs) proliferation and synovial hyperplasia are the main characters of osteoarthritis (OA) development. However, the role of FLSs and their proliferation in OA, and the underlying mechanisms, remain to be defined. We previous revealed that synovial macrophage M1 polarization exacerbates cartilage damage and experimental osteoarthritis, but its effect in FLSs proliferation and synovial hyperplasia are uncleared. Here, mRNA sequencing revealed that M1 macrophages highly produce GAS6 (Growth Arrest-specific Gene 6). Further study showed that GAS6 bind to Axl (one of GAS6 receptors) which was highly expressed in FLSs, resulted in promoting FLSs proliferation, implicating an important of GAS6/Axl in synovial hyperplasia and the pathogenesis of OA. Moreover, using transgenic mice with M1 or M2 macrophage polarized and OA mice as models, samples of OA patients and normal population, combined with co-culture model, this project aims to investigate the role and regulation mechanism of GAS6/Axl in FLSs proliferation and synovial hyperplasia of OA, on the molecular, cellular and animal levels. The study will provide potential target for prevention and treatment of OA.

滑膜增生是骨关节炎（Osteoarthritis，OA）的重要病理特征，成纤维样滑膜细胞过度增殖在OA滑膜增生中起重要作用，但其调控机制尚未阐明。申请人前期利用巨噬细胞分别向M1型或M2型极化增强的基因敲除小鼠OA模型，发现滑膜M1型巨噬细胞能促进软骨降解和OA进程，但其在成纤维样滑膜细胞增殖代谢和滑膜增生中的作用尚不清楚。申请人通过mRNA表达谱测序发现M1型巨噬细胞高表达GAS6，并且能作用于成纤维样滑膜细胞Axl受体，促进其细胞增殖，提示M1型巨噬细胞可能通过GAS6/Axl促进滑膜增生和OA进展。本项目拟通过临床病例标本，巨噬细胞极化增强的转基因小鼠OA模型，结合体外细胞共培养模型，明确极化型巨噬细胞在OA成纤维样滑膜细胞增殖代谢和滑膜增生中的作用，深入探讨GAS6/Axl轴介导滑膜巨噬细胞和成纤维样滑膜细胞在促进滑膜增生和OA发生发展中的作用及机制，为防治OA提供新的潜在靶点。

滑膜炎是骨关节炎（Osteoarthritis，OA）的超早期病理改变，是引起关节软骨损伤及维持骨关节炎病程进展的重要原因，其严重程度与关节肿胀、疼痛以及关节软骨进行性破坏呈正相关。课题负责人前期研究发现OA滑膜组织中M1型巨噬细胞极化增强，并通过分泌RSPO2、IL-6等炎症因子促进关节软骨破坏和OA病程，提示M1型巨噬细胞在OA滑膜炎中起重要作用。肥胖一直被认为是OA进展的重要危险因素，但OA滑膜炎中肥胖相关炎症的潜在调控机制尚不清楚。课题负责人通过结合临床病例标本、肥胖小鼠OA模型、体内外干预实验，初步阐明了肥胖相关OA滑膜炎症的潜在机制。研究发现，肥胖OA患者滑膜组织高度增生，滑膜组织中M1型巨噬细胞增多。另外，我们通过ApoE-/-肥胖OA模型，发现肥胖能促进OA小鼠滑膜巨噬细胞向M1亚型极化并加重滑膜炎症水平。机制研究发现，肥胖OA小鼠滑膜巨噬细胞胞葬功能受损，滑膜组织中凋亡细胞蓄积增多。干预实验研究发现，GAS6能通过调控巨噬细胞胞葬功能参与肥胖OA小鼠滑膜增生。该项目阐明了GAS6介导肥胖相关OA滑膜炎症的作用机制，靶向GAS6/Axl轴是防治OA的潜在策略。