Oncotarget

Research Papers:

Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-β signaling

Wei Zheng, Jialin Song, Yuanzheng Zhang, Shuai Chen, Hongjiang Ruan _ and Cunyi Fan

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Oncotarget. 2017; 8:101784-101794. https://doi.org/10.18632/oncotarget.21695

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Abstract

Wei Zheng1,*, Jialin Song1,*, Yuanzheng Zhang2,*, Shuai Chen1, Hongjiang Ruan1 and Cunyi Fan1

1Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

2Changhai Hospital of Second Military Medical University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Hongjiang Ruan, email: ruanhongjiang@126.com

Cunyi Fan, email: cyfan@sjtu.edu.cn

Keywords: metformin; peritendinous fibrosis; TGF-β; AMPK

Received: July 06, 2017    Accepted: September 20, 2017    Published: October 09, 2017

ABSTRACT

Injury-induced peritendinous adhesion is a critical clinical problem that leads to tendon function impairment. Therefore, it is very urgent to explore potential approaches to attenuate peritendinous adhesion formation. Recently, several studies have demonstrated the biological effect of metformin in inhibiting multiple tissue fibrosis. In this study, we performed in vitro and in vivo experiments to examine whether metformin prevents injury-induced peritendinous fibrosis. We found that tendon injury induced severe fibrosis formation in rats. However, orally administered metformin significantly alleviated the fibrosis based on macroscopic and histological evaluation. Peritendinous tissue from metformin-treated rats also showed decreased expression of fibrotic genes including col1a1, col3a1, and α-smooth muscle actin (α-SMA), and inhibition of transforming growth factor (TGF)-β1 signaling. The cell counting kit (CCK)-8, flow cytometry, and 5-ethynyl-2′-deoxyuridine (EdU) staining analyses showed that treatment of NIH/3T3 fibroblasts with metformin significantly inhibited excessive cell proliferation and promoted cell apoptosis. Metformin treatment also inhibited the expression of fibrotic genes and decreased the phosphorylation of smad2/3 and extracellular signal-regulated kinase (ERK) 1/2. Furthermore, blocking AMP-activated protein kinase (AMPK) signaling abolished the inhibitory effect of metformin on fibrosis. Our findings indicate that metformin has a protective role against peritendinous tissue fibrosis and suggest its clinical use could be a promising therapeutic approach.


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