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

作者全名："Zhu, Zhenglin; Huang, Yanran; Li, Jun; Yi, Dan; Liao, Junyi; Xiao, Jun; Xiao, Guozhi; Tong, Liping; Huang, Wei; Di, Chen"

作者地址："[Zhu, Zhenglin; Huang, Yanran; Yi, Dan; Tong, Liping; Di, Chen] Chinese Acad Sci, Shenzhen Inst Adv Technol, Res Ctr Comp Aided Drug Discovery, Shenzhen 518055, Peoples R China; [Zhu, Zhenglin; Huang, Yanran; Yi, Dan; Di, Chen] Chinese Acad Sci, Shenzhen Inst Adv Technol, Fac Pharmaceut Sci, Shenzhen 518055, Peoples R China; [Zhu, Zhenglin; Huang, Yanran; Liao, Junyi; Huang, Wei] Chongqing Med Univ, Dept Orthopaed Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Li, Jun] Rush Univ, Med Ctr, Dept Orthopaed Surg, Chicago, IL USA; [Xiao, Jun] Southern Med Univ, NanFang Hosp, Dept Orthopaed, Guangzhou 510515, Peoples R China; [Xiao, Guozhi] Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Peoples R China"

通信作者："Tong, LP; Di, C (通讯作者)，Chinese Acad Sci, Shenzhen Inst Adv Technol, Res Ctr Comp Aided Drug Discovery, Shenzhen 518055, Peoples R China.; Huang, W (通讯作者)，Chongqing Med Univ, Dept Orthopaed Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：JOURNAL OF ORTHOPAEDIC TRANSLATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000892218300003

JCR分区：Q1

影响因子：5.9

年份：2023

卷号：38

期号：　

开始页：158

结束页：166

文献类型：Article

关键词：Osteoarthritis; AMPK; ll-catenin; Phosphorylation; Metformin; Chondrocyte

摘要："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."

基金机构："National Natural Science Foundation of China (NSFC) [82030067, 82161160342, 82172397]; Youth Innovation Promotion Association of Chinese Academy of Sciences [2020353]; National Key Research and Development Program of China [2021YFB3800800]; China Postdoctoral Research Foundation [2021M703376]"

基金资助正文："This project has been supported by the National Natural Science Foundation of China (NSFC) grants (82030067, 82161160342 and 82172397) to D.C and L.T. and the grant from Youth Innovation Promotion Association of Chinese Academy of Sciences (2020353) to L.T. This work was also supported by National Key Research and Development Program of China (2021YFB3800800) to L.T. and D.C. D.Y. was supported by the grant of China Postdoctoral Research Foundation (2021M703376)."