细胞内骨桥蛋白介导TLR信号转导通路调控人工关节无菌性松动骨溶解的机制研究

Periprosthetic osteolysis is the most important complication after total joint arthroplasties. Aseptic loosening is the most important cause, but its mechanism is unknown. Pre-experimental results suggest that macrophages in the phantom-bone boundary membrane engulf the worn particles to produce inflammatory cells and induce osteoclast proliferation, activation, and osteolysis. Recent studies have shown that macrophages can produce high levels of intracellular osteopontin (iOPN); and iOPN can mediate phagocytic TLR9 signaling pathway induced by IFN-γ and proinflammatory cytokine production. OPNs of macrophages in the prosthetic-bone boundary membrane must be involved in some mechanism that affects the microenvironment. Assuming that iOPN acts as a linker in the TLRs signaling pathway of macrophages in the prosthetic-bone boundary membrane, it cooperates with MyD88 and IRAK1, activates MAPK and its corresponding signal pathway, activates target gene expression, regulates cytokines and affects the balance of inflammatory microenvironment. The aim of this project is to verify the hypothesis, clarify the mechanism of iOPN in macrophages in the phantom-bone boundary membrane, and provide a new clue for the prevention and treatment of aseptic loosening of total joint arthroplasties.

假体周围骨溶解是人工关节置换术后最主要的并发症，无菌性松动是最重要的原因，但其机制不明。预实验结果提示，假体-骨界膜中的巨噬细胞吞噬磨损颗粒产生炎性细胞，诱导破骨细胞增殖、活化，进而引起骨溶解。近期研究显示，巨噬细胞能产生高水平细胞内骨桥蛋白（iOPN）；而iOPN能介导巨噬细胞的TLR9信号通路致IFN-γ和促炎性细胞因子的产生。假体-骨界膜中的巨噬细胞的OPN必定参与了影响微环境的某种机制。假设：iOPN作为假体-骨界膜组织巨噬细胞中TLRs信号途径中的接头分子，与MyD88及IRAK1协同作用，激活MAPK及其相应的信号通路，启动靶基因表达，从而调节细胞因子，影响炎症微环境的平衡。本项目拟通过验证假设，明确界膜巨噬细胞中iOPN的作用机制，为人工关节无菌性松动的预防和治疗提供新线索。

假体周围骨溶解是人工关节置换术后最主要的并发症，无菌性松动是最重要的原因，但其机制不明。预实验结果提示，假体-骨界膜中的巨噬细胞吞噬磨损颗粒产生炎性细胞，诱导破骨细胞增殖、活化，进而引起骨溶解。近期研究显示，巨噬细胞能产生高水平细胞内骨桥蛋白（iOPN）；而iOPN能介导巨噬细胞的TLR9信号通路致IFN-γ和促炎性细胞因子的产生。假体-骨界膜中的巨噬细胞的OPN必定参与了影响微环境的某种机制。假设：iOPN作为假体-骨界膜组织巨噬细胞中TLRs信号途径中的接头分子，与MyD88及IRAK1协同作用，激活MAPK及其相应的信号通路，启动靶基因表达，从而调节细胞因子，影响炎症微环境的平衡。本项目通过验证假设，明确界膜巨噬细胞中iOPN的作用机制，为人工关节无菌性松动的预防和治疗提供新线索。