Mechanical overloading leads to chondrocyte degeneration and senescence via Zmpste24-mediated nuclear membrane instability

• Published in: iScience Vol. 26; no. 11; p. 108119
• Main Authors: Kong, Keyu, Jin, Minghao, Zhao, Chen, Qiao, Hua, Chen, Xuzhuo, Li, Baixing, Rong, Kewei, Zhang, Pu, Shan, Yu, Xu, Zhengquan, Chang, Yongyun, Li, Huiwu, Zhai, Zanjing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.11.2023; Elsevier
• Subjects: Biological sciences; Molecular biology; Physiology; Molecular biology; Biological sciences; Physiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.108119

Patients with OA and varus knees are subject to abnormal mechanical environment and objective of this study was to investigate the molecular mechanisms underlying chondrocyte senescence caused by mechanical overloading and the role of Zmpste24-mediated nuclear membrane instability in varus knees. Finite element analysis showed that anteromedial region of tibial plateau experienced the most mechanical stress in an osteoarthritis patient with a varus knee. Immunohistochemistry exhibited lower Zmpste24 expression and higher expression of senescence marker p21 in the anteromedial region. Animal experiments and cell-stretch models also demonstrated an inverse relationship between Zmpste24 and mechanically induced senescence. Zmpste24 overexpression rescued cartilage degeneration and senescence in vitro by scavenging ROS. In conclusion, anteromedial tibial plateau is exposed to abnormal stress in varus knees, downregulation of Zmpste24, and nuclear membrane stability may explain increased senescence in this region. Zmpste24 and nuclear membrane stability are potential targets for treating osteoarthritis caused by abnormal alignment. [Display omitted] •Patients with varus knee experience most stress in the anteromedial tibial plateau•Zmpste24 expression decreases and nuclear instability happens under excessive stress•Zmpste24 overexpression rescues chondrocyte senescence caused by excessive stress Biological sciences; Physiology; Molecular biology