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

Keyu Kong; Minghao Jin; Chen Zhao; Hua Qiao; Xuzhuo Chen; Baixing Li; Kewei Rong; Pu Zhang; Yu Shan; Zhengquan Xu; Yongyun Chang; Huiwu Li; Zanjing Zhai

doi:10.1016/j.isci.2023.108119

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

iScience. 2023 Oct 4;26(11):108119. doi: 10.1016/j.isci.2023.108119. eCollection 2023 Nov 17.

Authors

Keyu Kong¹, Minghao Jin¹, Chen Zhao¹, Hua Qiao¹, Xuzhuo Chen², Baixing Li¹, Kewei Rong¹, Pu Zhang¹, Yu Shan³, Zhengquan Xu⁴, Yongyun Chang¹, Huiwu Li¹, Zanjing Zhai¹

Affiliations

¹ Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
² Shanghai Key Laboratory of Stomatology, Department of Oral Surgery, College of Stomatology, Ninth People's Hospital, Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Suzhou Ninth People's Hospital, Department of Orthopedics, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou, China.
⁴ Suzhou Municipal Hospital, Department of Orthopedics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China.

Abstract

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.

Keywords: Biological sciences; Molecular biology; Physiology.