Metformin improves fibroblast metabolism and ameliorates arthrofibrosis in rats

作者全名："Zhu, Zhenglin; Gao, Shengqiang; Zhu, Hui; Chen, Yi; Wu, Dandong; Chen, Zhiyu; Huang, Yanran; Wu, Xiangdong; Hu, Ning; Chen, Di; Huang, Wei; Chen, Hong"

作者地址："[Zhu, Zhenglin; Gao, Shengqiang; Chen, Zhiyu; Huang, Yanran; Hu, Ning; Huang, Wei; Chen, Hong] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing, Peoples R China; [Zhu, Zhenglin; Gao, Shengqiang; Chen, Zhiyu; Huang, Yanran; Hu, Ning; Huang, Wei; Chen, Hong] Chongqing Med Univ, Orthoped Lab, Chongqing, Peoples R China; [Zhu, Hui] Chongqing Med Univ, Affiliated Hosp 1, Dept Ultrasound, Chongqing, Peoples R China; [Chen, Yi] Chongqing Med Univ, Affiliated Hosp 2, Dept Rehabil, Chongqing, Peoples R China; [Wu, Dandong] Chongqing Med Univ, Affiliated Hosp 1, Dept Rehabil, Chongqing, Peoples R China; [Wu, Xiangdong] Peking Univ, Beijing Jishuitan Hosp, Sch Clin Med 4, Dept Orthopaed Surg, Beijing, Peoples R China; [Chen, Di] Chinese Acad Sci, Res Ctr Comp Aided Drug Discovery, Shenzhen Institue Adv Technol, Shenzhen, Peoples R China; [Chen, Di] Chinese Acad Sci, Shenzhen Inst Adv Technol, Fac Pharmaceut Sci, Shenzhen, Peoples R China; [Chen, Hong] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, 1 Youyi Rd, Chongqing 400016, Peoples R China"

通信作者："Huang, W; Chen, H (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing, Peoples R China.; Chen, D (通讯作者)，Chinese Acad Sci, Res Ctr Comp Aided Drug Discovery, Shenzhen Institue Adv Technol, Shenzhen, Peoples R China.; Chen, H (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF ORTHOPAEDIC TRANSLATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001028242900001

JCR分区：Q1

影响因子：6.6

年份：2023

卷号：40

期号：　

开始页：92

结束页：103

文献类型：Article

关键词：Arthrofibrosis; Fibroblast; Glycolysis; Metabolic reprogramming; Metformin

摘要："Background: 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.Methods: 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.Results: We found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated infiammatory 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 infiux 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.Conclusion: 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."

基金机构：Chongqing Natural Science Foundation [cstc2019jcyj-msxmX0831]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN202000430]; Chongqing Medical Scientific Research Project [2021MSXM032]

基金资助正文：This work was supported by the Chongqing Natural Science Foundation [Grant No. cstc2019jcyj-msxmX0831]; the Science and Technology Research Program of Chongqing Municipal Education Commission [Grant No. KJQN202000430]; and the Chongqing Medical Scientific Research Project [Grant No. 2021MSXM032].