基于关节微环境失稳致线粒体功能障碍和线粒体自噬紊乱探讨补骨脂素防治骨关节炎的机制

The pathogenesis of Osteoarthritis (OA) is complicated. Chondrocyte dysfunction, impairment of repair and apoptosis are the cytological basis of cartilage degeneration. Leptin level abnormal and other stress factors can affect the metabolic activity of chondrocytes and cartilage microenvironment homeostasis, causing cartilage injury and dysfunction of mitochondria, to induce cell dysfunction and apoptosis of cartilage, accelerate OA cartilage degeneration, together with mitochondrial autophagy disorders of cartilage. Our previous studies found that psoralen may inhibit the mitochondrial damage of chondrocytes by regulating the level of leptin in articular fluid and cartilage, and regulate the key molecules in the mitochondrial autophagy pathway of cartilage cells, so as to improve the structure and function of cartilage and subchondral bone. This project aims to study the effect and molecular mechanism of psoralen on regulating leptin level and OA cartilage microenvironment, and regulateing the dynamic balance of cartilage metabolism, inhibiting of mitochondrial damage, targeting PINK1/Parkin signaling pathway in chondrocyte mitochondrial autophagy regulation, promote cartilage repair, inhibited the apoptosis of cartilage cells, play a role of the prevention and treatment of OA. It provides new research ideas and potential therapeutic targets for the research of the pathogenesis and treatment of OA, and provides experimental basis for potential OA therapy.

骨关节炎（Osteoarthritis，OA）病机复杂，软骨细胞功能障碍、损伤修复障碍和细胞凋亡是软骨退变的细胞学基础。瘦素水平异常等应激因素可影响软骨细胞代谢活性及软骨生存微环境稳态，导致软骨细胞线粒体损伤和功能障碍，协同OA软骨细胞线粒体自噬紊乱，共同诱导软骨细胞功能障碍和凋亡，加速OA软骨退变。前期研究发现，补骨脂素可能通过调节关节液及软骨中瘦素水平，抑制软骨细胞线粒体损伤，调节软骨细胞线粒体自噬通路上的关键分子，改善软骨及软骨下骨结构和功能。本项目拟深入研究补骨脂素调控OA软骨中瘦素等水平调节关节微环境和软骨代谢的动态平衡，抑制线粒体损伤，同时靶向PINK1/Parkin信号通路激活软骨细胞内线粒体自噬调控，促进软骨细胞修复，抑制软骨细胞凋亡，防治OA的作用和分子机制。本项目将为OA的发病机制研究和治疗提供新的研究思路和潜在的治疗靶点，为有潜力的OA治疗药物研发提供实验依据。

骨关节炎（OA）是老年人最常见的慢性关节退行性疾病，研究表明线粒体自噬与骨关节炎的发病机制可能密切相关，线粒体自噬功能障碍可导致软骨细胞死亡，细胞外基质稳态失调或软骨退变。本课题以线粒体自噬为主要切入点，通过分子生物学技术与荧光染色技术探索了软骨细胞线粒体膜电位及自噬状态的变化，探索瘦素和补骨脂素在OA软骨细胞线粒体自噬机制中的作用，进一步阐释瘦素和补骨脂素在在OA发病机理中的重要作用。主要研究内容及结果：以软骨细胞线粒体自噬为切入点，从分子机制上部分验证了瘦素对OA发展的促进作用，并论证了瘦素对线粒体自噬的抑制机制，可为OA治疗提供新的靶点。由此我们推断，瘦素可通过抑制Parkin及LC3B等自噬蛋白表达，同时促进MMP-13表达，一定程度上抑制软骨细胞线粒体自噬。此外，瘦素可能通过降低线粒体膜电位使线粒体功能受损，同时抑制软骨细胞线粒体自噬，促进细胞分解代谢，进而促进OA的进展。同时发现补骨脂素一定程度上可促进Parkin蛋白表达进而促进线粒体自噬，发挥保护软骨细胞的作用，为临床OA发病机制的研究提供新的思路和理论指导，为中医传统的药物治疗提供了理论依据与实验基础。