2. Academic Validation
  3. AIDS patients suffer higher risk of advanced knee osteoarthritis progression due to lopinavir-induced Zmpste24 inhibition

AIDS patients suffer higher risk of advanced knee osteoarthritis progression due to lopinavir-induced Zmpste24 inhibition

  • Bone Res. 2025 Jun 3;13(1):58. doi: 10.1038/s41413-025-00431-2.
Keyu Kong # 1,  Li Liu # 2,  Renfang Zhang # 2,  Yongyun Chang 1,  Yueming Shao 2,  Chen Zhao 1,  Hua Qiao 1,  Minghao Jin 1,  Xuzhuo Chen 3,  Wentao Shi 4,  Xinru Wu 1,  Wenxuan Fan 1,  Yuehao Hu 1,  Kewei Rong 1,  Pu Zhang 1,  Baixing Li 1,  Jingwei Zhang 1,  Peixiang Ma 1,  Xiaoling Zhang 5,  Huiwu Li 6,  Zanjing Zhai 7
Affiliations

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 Department of Infection and Immunity, Shanghai Public Health Clinical Center (SPHCC), Fudan University, Shanghai, China.
  • 3 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.
  • 4 Department of Biostatistics in Clinical Research Unit, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 5 Department of Orthopedic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. xlzhang@shsmu.edu.cn.
  • 6 Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. huiwu1223@163.com.
  • 7 Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. zanjing_zhai@163.com.
  • # Contributed equally.
PMID: 40461512 DOI: 10.1038/s41413-025-00431-2
Abstract

Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome (AIDS) patients has remained contentious, with conjectures pointing towards its correlation with distinct Antiviral regimes. Protease Inhibitors (PIs) stand as a prominent class of Antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence. This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis (OA) development and explore the molecular mechanisms underlying this association. A retrospective cohort of 151 HIV-infected individuals, categorized into PI and non-PI groups, was established. Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group. Additionally, 25 anti-HIV drugs were screened and among all Antiviral drugs, lopinavir had the most detrimental impact on cartilage anabolism, accelerating cartilage senescence and promoting mouse OA development. Mechanistically, lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability, which leads to decreased binding between nuclear membrane-binding protein USP7 and MDM2 and activates USP7/MDM2/p53 pathway. Zmpste24 overexpression reduces OA severity in mice. These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition, which provides new insights into the selection of HIV regimens.

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