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

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.

Macrophage-Derived miRNA-Containing Exosomes Induce Peritendinous Fibrosis after Tendon Injury through the miR-21-5p/Smad7 Pathway

“…To further investigate the mechanisms underlying miR-21-5p-induced fibrogenesis in tenocytes, we chose Smad7 as a candidate gene because of its close involvement in inflammation and fibrosis 35, 36, 50, 51. Previous studies have demonstrated that TGF-β1/SMAD signaling contributes to the formation of adhesions around healing digital flexor tendons9, 52 and that blocking of the TGF-β1 pathway could prevent the formation of tendon adhesions 38 . Our transfection data revealed that BMDM exosomes containing mostly miR-21-5p reduced Smad7 expression, suggesting that exosomal miR-21-5p could activate the TGF-β1 pathway in tendon by reducing Smad7 expression.…”

Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy

“…Peritendinous fibrosis, a unique pathological tissue fibrosis, mostly occurs after tendon injury, tendon surgery, and joint immobilization. Several mechanisms have been implicated in the modulation of adhesion formation, including the regulation of the inflammatory response ( Chen et al, 2017 ), and the TGF signaling pathway ( Jiang et al, 2014 ; Zheng et al, 2017 ). The present study, for the first time, to our knowledge, examines the relationship between autophagy and peritendinous fibrosis, and demonstrates protective roles of autophagy in fibrogenesis.…”

Integrated analysis of long non-coding RNAs and mRNAs associated with peritendinous fibrosis

“…Another lncRNA, HOXD-AS1, has been reported to upregulate JAK/STAT target genes, including COX-1 and caspase-1 [21]. In recent years, aberrant arrest of the cell cycle has been shown to be critical in fibrogenesis; additionally, excessive cell proliferation and increased G2/M arrest have been observed in peritendinous fibrosis [22]. Furthermore, Li showed that Atg5 interference promoted G2/M phase arrest in proximal tubular epithelial cells and exacerbated subsequent renal fibrosis [23].…”