The novel HSP90 monoclonal antibody 9B8 ameliorates articular cartilage degeneration by inhibiting glycolysis via the HIF-1 signaling pathway
Shunan Yu,
Xiong Shu,
Xinyu Wang,
Yueyang Sheng,
Shan Li,
Ying Wang,
Yanzhuo Zhang,
Jiangfeng Tao,
Xu Jiang,
Chengai Wu
Affiliations
Shunan Yu
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Xiong Shu
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Xinyu Wang
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Yueyang Sheng
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Shan Li
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Ying Wang
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Yanzhuo Zhang
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Jiangfeng Tao
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China
Xu Jiang
Department of Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing Research Institute of Traumatology and Orthopaedics, Beijing, 100035, PR China; Corresponding author. Department of Orthopaedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, PR China.
Chengai Wu
Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, PR China; Corresponding author. Chengai Wu, Department of Molecular Orthopedics, Beijing Research Institute of Traumatology and Orthopedics, National Center for orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, PR China.
Osteoarthritis (OA) is a prevalent chronic degenerative disease that affects the bones and joints, particularly in middle-aged and elderly individuals. It is characterized by progressive joint pain, swelling, stiffness, and deformity. Notably, treatment with a heat shock protein 90 (HSP90) inhibitor has significantly curtailed cartilage destruction in a rat model of OA. Although the monoclonal antibody 9B8 against HSP90 is recognized for its anti-tumor properties, its potential therapeutic impact on OA remains uncertain. This study investigated the effects of 9B8 on OA and its associated signaling pathways in interleukin-1β (IL-1β)−stimulated human chondrocytes and a rat anterior cruciate ligament transection (ACLT) model. A specific concentration of 9B8 preserved cell viability against IL-1β−induced reduction. In vitro, 9B8 significantly reduced the expression of extracellular matrix-degrading enzyme such as disintegrin and metallopeptidase-4 (ADAMTS4) of thrombospondin motifs, matrix metalloproteinase-13 (MMP-13), as well as cellular inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which were upregulated by IL-1β.In vivo, 9B8 effectively protected the articular cartilage and subchondral bone of the rat tibial plateau from ACLT-induced damage. Additionally, gene microarray analysis revealed that IL-1β substantially increased the expression of SLC2A1, PFKP, and ENO2 within the HIF-1 signaling pathway, whereas 9B8 suppressed the expression of these genes. Thus, 9B8 effectively mitigates ACLT-induced osteoarthritis in rats by modulating the HIF-1 signaling pathway, thereby inhibiting overexpression involved in glycolysis.These results collectively indicate that 9B8 is a promising novel drug for the prevention and treatment of OA.
