TFF3通过诱导早期骨关节炎中滑膜巨噬细胞M1型极化促进软骨退变的作用及机制研究

骨关节炎（osteoarthritis, OA）中M1型滑膜巨噬细胞主导的滑膜炎是推动软骨退变的重要原因。早期OA即可发生上述滑膜炎改变，但是早期OA中诱导滑膜巨噬细胞M1型极化及相关炎症的原因和机制不明。我们预实验发现早期OA软骨细胞及关节液中TFF3表达上调，TFF3可显著促进滑膜巨噬细胞M1型极化，进一步发现CCR2受体和STAT1通路可能参与介导TFF3的调控作用。据此提出假说：早期OA中TFF3作用于CCR2受体激活STAT1通路，诱导滑膜巨噬细胞M1型极化及滑膜炎，进而促进软骨退变。本项目拟从分子、细胞、动物模型和患者标本等多层次展开研究：①明确TFF3通过诱导早期OA滑膜巨噬细胞M1型极化促进软骨退变的关键作用；②阐明TFF3促进滑膜巨噬细胞M1型极化的具体分子机制；③探索靶向抑制TFF3对于OA的治疗作用。此将为揭示OA发病机制、筛选新型治疗靶点提供理论依据。

M1-polarized synovial macrophages-mediated synovitis is one of the major risk factors of the degeneration of articular cartilage in osteoarthritis (OA), and is commonly found in early OA. However, in early OA, the factors inducing pro-inflammatory M1 polarization of synovial macrophages remain unknown. Our previous work showed that the expression of trefoil factor 3 (TFF3) was significantly elevated in chondrocytes and synovial fluid in early OA, and TFF3 could mediate M1 polarization of macrophages, during which CC Chemokine Receptor 2 (CCR2) and signal transducer and activator of transcription 1 (STAT1) may play a critical role. Thus, we hypothesized that in early OA, TFF3 causes M1 polarization of synovial macrophages through CCR2-STAT1 signaling, which subsequently promotes degeneration of chondrocytes. Further, we will reveal the biological function of TFF3 in promoting M1 polarization of synovial macrophages in early OA, and the detailed mechanisms underlying TFF3-induced M1 polarization of macrophages. Besides, we will study whether TFF3 could be a potent therapeutic target for OA. Thus, this study will provide a new insight in the pathogenesis of OA, and a novel strategy for the treatment of OA via targeting macrophages to regulate the inflammatory microenvironment.