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

安普克 磷酸化 细胞生物学 信号转导 软骨细胞 化学 连环素 激活剂(遗传学) 二甲双胍 蛋白激酶A 内分泌学 内科学 Wnt信号通路 生物 医学 生物化学 基因 体外 糖尿病
作者
Zhenglin Zhu,Yanran Huang,Jun Li,Dan Yi,Junyi Liao,Jun Xiao,Guozhi Xiao,Liping Tong,Wei Huang,Di Chen
出处
期刊:Journal of orthopaedic translation [Elsevier BV]
卷期号:38: 158-166 被引量:10
标识
DOI:10.1016/j.jot.2022.10.005
摘要

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.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.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.These findings suggest that metformin may exert its chondro-protective effect at least in part through the inhibition of β-catenin signaling in chondrocytes.This study demonstrated the interaction between AMPK and β-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.
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