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

Zhu，Zhenglin1,2,3; Huang，Yanran1,2,3; Li，Jun4; Yi，Dan1,2; Liao，Junyi3; Xiao，Jun5; Xiao，Guozhi6; Tong，Liping1; Huang，Wei3; Di，Chen1,2

2023

10.1016/j.jot.2022.10.005

Journal of Orthopaedic Translation   Impact Factor & Quartile

2214-031X

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 phosphorylation and β-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes. Results: We found that metformin inhibited β-catenin 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 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.

AMPK Chondrocyte Metformin Osteoarthritis Phosphorylation β-catenin

SCI

English

Others

Chinese Academy of Sciences[2020353];Postdoctoral Research Foundation of China[2021M703376];National Key Research and Development Program of China[2021YFB3800800];National Natural Science Foundation of China[82030067];National Natural Science Foundation of China[82161160342];National Natural Science Foundation of China[82172397];

Orthopedics

Orthopedics

WOS:000892218300003

ELSEVIER

2-s2.0-85141803250

Scopus

1.Research Center for Computer-Aided Drug Discovery,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,518055,China
2.Faculty of Pharmaceutical Sciences,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,518055,China
3.Department of Orthopaedic Surgery,The First Affiliated Hospital of Chongqing Medical University,Chongqing,400016,China
4.Department of Orthopaedic Surgery,Rush University Medical Center,Chicago,United States
5.Department of Orthopaedics,NanFang Hospital,Southern Medical University,Guangzhou,510515,China
6.School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China

Zhu，Zhenglin,Huang，Yanran,Li，Jun,et al. AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes[J]. Journal of Orthopaedic Translation,2023,38:158-166.

Zhu，Zhenglin.,Huang，Yanran.,Li，Jun.,Yi，Dan.,Liao，Junyi.,...&Di，Chen.(2023).AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes.Journal of Orthopaedic Translation,38,158-166.

Zhu，Zhenglin,et al."AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes".Journal of Orthopaedic Translation 38(2023):158-166.