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

Journal of Orthopaedic TranslationVolume 38, January 2023, Pages 158-166Journal of Orthopaedic TranslationAuthor links open overlay panelAbstractBackground

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-cateninS552 phosphorylation and β-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes.

Results

We found that metformin inhibited β-cateninS552 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-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 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.

Keywords

Osteoarthritis

AMPK

β-catenin

Phosphorylation

Metformin

Chondrocyte

© 2022 Published by Elsevier B.V. on behalf of Chinese Speaking Orthopaedic Society.

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