AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes
Zhenglin Zhu, Yanran Huang, Jun Li, Dan Yi, Junyi Liao, Jun Xiao, Guozhi Xiao, Liping Tong, Wei Huang, Di Chen
Abstract
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 β-catenin signaling could lead to OA development; however, the upstream regulatory mechanisms of β-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 5′-monophosphate-activated protein kinase (AMPK) activator. Westerrn blot analysis, luciferase reporter assay and immunofluorescent (IF) staining were performed to examine changes in β-catenin S552 phosphorylation and β-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes. Results We found that metformin inhibited β-catenin S552 phosphorylation in ATDC5 cells and in primary chondrocytes in a time-dependent manner. Metformin inhibited β-catenin nuclear translocation and β-catenin reporter activity. In addition, metformin also attenuated the expression of β-catenin downstream target genes. We also demonstrated that metformin inhibited β-catenin S552 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 β-catenin signaling in chondrocytes. The translational potential of this article This study demonstrated the interaction between AMPK and β-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.