Metformin improves fibroblast metabolism and ameliorates arthrofibrosis in rats

二甲双胍 关节炎 医学 糖酵解 厌氧糖酵解 内分泌学 药理学 成纤维细胞 纤维化 内科学 化学 新陈代谢 胰岛素 生物化学 病理 替代医学 体外
作者
Zhenglin Zhu,Shengqiang Gao,Hui Zhu,Yi Chen,Dandong Wu,Zhiyu Chen,Yanran Huang,Xiangdong Wu,Ning Hu,Di Chen,Wei Huang,Hong Chen
出处
期刊:Journal of orthopaedic translation [Elsevier]
卷期号:40: 92-103 被引量:6
标识
DOI:10.1016/j.jot.2023.05.011
摘要

Emerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has beneficial effect on arthrofibrosis and its underlying mechanism.Articular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation.We found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion (ROM) of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin.Metformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis.The translational potential of this article: The findings of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.
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