Anti-fibrotic action of pirfenidone in Dupuytren’s disease-derived fibroblasts

BMC Musculoskeletal Disorders

Research Article

Mark E. Baratz¹  Phillip H. Gallo²  Fang Liu²  Chaoming Zhou²  Latha Satish³  Sandeep Kathju³ 

[1] Department of Orthopaedic Surgery, University of Pittsburgh, 15261, Pittsburgh, PA, USA;Department of Plastic Surgery, University of Pittsburgh, 15261, Pittsburgh, PA, USA;McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA;Department of Plastic Surgery, University of Pittsburgh, 3550 Terrace Street, Scaife Hall, S685.2, 15261, Pittsburgh, PA, USA;

关键词: Dupuytren’s contracture;    Palmar fascia fibrosis;    Carpal tunnel;    Collagen;    Alpha-SMA;    Smad2/Smad3;    Cell migration;    Cell contraction;   

DOI  :  10.1186/s12891-016-1326-y

 received in 2016-06-22, accepted in 2016-11-03,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundDupuytren’s disease (DD) is a complex fibro-proliferative disorder of the hand that is often progressive and eventually can cause contractures of the affected fingers. Transforming growth factor beta (TGF-β1) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in DD. Pirfenidone (PFD) is an active small molecule shown to inhibit TGF-β1-mediated action in other fibrotic disorders. This study investigates the efficacy of PFD in vitro in inhibiting TGF-β1-mediated cellular functions leading to Dupuytren’s fibrosis.MethodsFibroblasts harvested from (DD) and carpal tunnel (CT)- tissues were treated with or without TGF-β1 and/or PFD and were subjected to cell migration, cell proliferation and cell contraction assays. ELISA; western blots and real time RT-PCR assays were performed to determine the levels of fibronectin; p-Smad2/Smad3; alpha-smooth muscle actin (α-SMA), α2 chain of type I collagen and α1 chain of type III collagen respectively.ResultsOur results show that PFD effectively inhibits TGF-β1-induced cell migration, proliferation and cell contractile properties of both CT- and DD-derived fibroblasts. TGF-β1−induced α-SMA mRNA and protein levels were inhibited at the higher concentration of PFD (800 μg/ml). Interestingly, TGF-β1 induction of type I and type III collagens and fibronectin was inhibited by PFD in both CT- and DD- derived fibroblasts, but the effect was more prominent in DD cells. PFD down-regulated TGF-β1-induced phosphorylation of Smad2/Smad3, a key factor in the TGF-β1 signaling pathway.ConclusionTaken together these results suggest the PFD can potentially prevent TGF-β1−induced fibroblast to myofibroblast transformation and inhibit ECM production mainly Type I- and Type III- collagen and fibronectin in DD-derived fibroblasts. Further in-vivo studies with PFD may lead to a novel therapeutic application in preventing the progression or recurrence of Dupuytren’s disease.

【 授权许可】

CC BY   
© The Author(s). 2016