AUTHOR=Zheng Wei , Qian Yun , Chen Shuai , Ruan Hongjiang , Fan Cunyi 

TITLE=Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00402

DOI=10.3389/fphar.2018.00402

ISSN=1663-9812

ABSTRACT=<p>Dysregulation of autophagy plays a pivotal role in fibrosis in multiple organs. However, the role of autophagy in peritendinous fibrosis is not well understood. Here, we hypothesize that autophagy plays a protective role in preventing adhesion formation. In a rat model of tendon injury, we observed dysregulated autophagy during excessive extracellular matrix deposition. Pharmacological induction of autophagy by rapamycin markedly alleviated the severity of peritendinous fibrosis <italic>in vivo</italic>. In NIH/3T3 fibroblasts and tenocytes, transforming growth factor β1 (TGF-β1) markedly activated myofibroblasts and increased collagen synthesis. Addition of rapamycin activated autophagy, reduced collagen synthesis, and suppressed myofibroblast activation. <italic>In vitro</italic> experiments also showed that rapamycin decreased cell proliferation and increased the number of cells arrested in G<sub>0</sub>/G<sub>1</sub> phase. However, following pretreatment with the autophagy inhibitor 3-methyladenine (3-MA), rapamycin was unable to repress the fibrotic changes induced by TGF-β1. Autophagy related protein 5 (<italic>Atg5</italic>) RNA interference in fibroblasts also abolished the protective effects of rapamycin <italic>in vitro</italic>. In conclusion, our results point to rapamycin as a potential treatment strategy in the prevention of peritendinous fibrosis after tendon injury.</p>