AMPK activator decelerates osteoarthritis development by inhibition of ?-catenin signaling in chondrocytes

Authors：Zhu, Zhenglin; Huang, Yanran; Li, Jun; Yi, Dan; Liao, Junyi; Xiao, Jun; Xiao, Guozhi; Tong, Liping^*; Huang, Wei^*; Di, Chen^*

Source：Journal of Orthopaedic Translation, 2023, 38: 158-166.

DOI：10.1016/j.jot.2022.10.005

• Osteoarthritis
• AMPK
• ll-catenin
• Phosphorylation
• Metformin
• Chondrocyte

Background: Osteoarthritis (OA) is a common degenerative joint disease with significant negative impact on the quality of life. It has been reported that abnormal upregulation of ll-catenin signaling could lead to OA development; however, the upstream regulatory mechanisms of ll-catenin signaling have not been determined. Methods: Primary rat chondrocytes and ATDC5 chondrocyte cell line were stimulated with AKT2 and treated with or without metformin, an adenosine 50-monophosphate-activated protein kinase (AMPK) activator. Westerrn blot analysis, luciferase reporter assay and immunofluorescent (IF) staining were performed to examine changes in ll-cateninS552 phosphorylation and ll-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes. Results: We found that metformin inhibited ll-cateninS552 phosphorylation in ATDC5 cells and in primary chondrocytes in a time-dependent manner. Metformin inhibited ll-catenin nuclear translocation and ll-catenin reporter activity. In addition, metformin also attenuated the expression of ll-catenin downstream target genes. We also demonstrated that metformin inhibited ll-cateninS552 phosphorylation in articular cartilage in mice. Conclusion: These findings suggest that metformin may exert its chondro-protective effect at least in part through the inhibition of ll-catenin signaling in chondrocytes. The translational potential of this article: This study demonstrated the interaction between AMPK and ll-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.

• Institution
  1; 南方医科大学; 中国科学院