Therapeutic restoration of mitochondria–endoplasmic reticulum cross talk for osteoarthritis
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Mingzhuang Hou
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Yifan Ma
Yaoge Deng
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Yubin Wu
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Yanrun Zhu
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Yang Liu
Xiaoping Li
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Lili Yu
Zirui He
Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology
Yifan Wang
Shiyan Dong
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center
Xiaowei Xia
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Jianfeng Yu
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Chenqi Yu
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Kang Kang
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Yingjie Lu
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Lili Sun
Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology
Betty Y. S. Kim
Yuan Yuan
Yijian Zhang
Department of Orthopaedics, First Affiliated Hospital of Soochow University
Wen Jiang
Xuesong Zhu
Department of Orthopaedics, First Affiliated Hospital of Soochow University