AMPK/SIRT3正反馈环路介导的软骨细胞线粒体质量控制在骨关节炎中的作用及机制研究

软骨退变是骨关节炎（OA）的核心特征，而软骨细胞代谢对软骨稳态起决定性作用。近年发现线粒体作为软骨细胞的能量工厂和代谢调控中心，其功能障碍是OA发病的关键环节，维持软骨细胞线粒体质量控制（MQC）平衡是治疗OA的潜在策略。SIRT3是线粒体最主要的去乙酰化酶，其缺失可导致软骨细胞线粒体功能障碍并诱发OA；而AMPK是软骨细胞代谢关键调控分子，维持细胞能量平衡，其活性降低也会诱发OA。既往发现软骨细胞中AMPK和SIRT3的表达/活性保持一致，但并无研究探索两者在软骨细胞中的互调机制及对MQC的作用。综合文献和课题组前期结果发现：软骨细胞中AMPK/SIRT3具有形成正反馈环路并调控MQC的潜能。本项目拟从多种OA模型体外和体内验证软骨细胞AMPK/SIRT3正反馈环路并研究其对线粒体氧化应激、生物发生、动力学和自噬等MQC关键过程的调控作用及机制，为OA发病理论和治疗靶点探索提供新的思路。

Cartilage degeneration is a core feature of osteoarthritis (OA), and chondrocyte metabolism plays a critical role in cartilage homeostasis. In recent years, it has been found that mitochondria are the centres for energy production and metabolic regulation in chondrocytes, and chondrocyte mitochondrial dysfunction is a key event in OA pathogenesis, indicating that maintaining the balance of chondrocyte mitochondrial mass control (MQC) is a potential strategy for OA treatment. SIRT3 is the most important deacetylase in mitochondria, and its deletion can lead to chondrocyte mitochondrial dysfunction and induce OA development; meanwhile, AMPK is a key regulator of chondrocyte metabolism and maintains cell energy balance, and decreased AMPK activity can also induce OA development. Previous studies have found that the expression / activity of AMPK and SIRT3 in chondrocytes are always consistent, but no studies have explored the mutual regulatory mechanisms of both and their effect on MQC in chondrocytes. Based on the results of previous studies and the preliminary results of our group, we speculate that that AMPK/SIRT3 has the potential to form a positive feedback loop and regulate MQC in chondrocytes. This project aims to validate the AMPK/SIRT3 positive feedback loop in chondrocytes, and to study its regulatory effects and mechanisms on the key biological processes of MQC, including mitochondrial oxidative stress, biogenesis, dynamics and mitophagy in vitro and in vivo from various OA models, so as to provide new ideas for the subsequent studies on the pathogenesis and therapeutic targets of OA.