Hou Mingzhuang, Ma Yifan, Deng Yaoge, Wu Yubin, Zhu Yanrun, Liu Yang, Li Xiaoping, Yu Lili, He Zirui, Wang Yifan, Dong Shiyan, Xia Xiaowei, Yu Jianfeng, Yu Chenqi, Kang Kang, Lu Yingjie, Sun Lili, Kim Betty Y S, Yuan Yuan, Zhang Yijian, Jiang Wen, Zhu Xuesong
Department of Orthopaedics, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Orthopaedic Institute, Suzhou Medical College, Soochow University, Suzhou 215000, China.
Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2426992122. doi: 10.1073/pnas.2426992122. Epub 2025 Sep 2.
Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial-endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.
骨关节炎是老年人群中一种常见的关节疾病。骨关节炎的标志是关节软骨退变，其特征是软骨细胞发生变化，包括线粒体功能障碍。然而，这种变化如何影响软骨细胞内稳态以及这些过程是否可作为骨关节炎的治疗靶点，其确切机制仍不清楚。在此，我们表明，软骨细胞中因线粒体融合蛋白2（MFN2）表达缺失导致的线粒体功能受损和软骨基质代谢紊乱会引发骨关节炎。沉默调节蛋白3（SIRT3）是线粒体功能的关键调节因子，在调节MFN2以恢复线粒体动力学、减少碎片化并维持软骨细胞线粒体功能方面发挥着关键作用。具体而言，SIRT3直接使MFN2去乙酰化并间接使其去泛素化，防止其降解。MFN2介导的线粒体-内质网（ER）连接支持细胞内稳态，减轻内质网应激并维持线粒体钙离子平衡，这些共同减轻软骨细胞衰老。用MFN2 mRNA构建的细胞外囊泡有效预防了骨关节炎小鼠的软骨退变并恢复了其运动能力。这些发现表明，靶向MFN2是预防软骨退变和缓解骨关节炎进展的一种有前景的策略。
