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Anti-fibrotic action of pirfenidone in Dupuytren?s disease-derived fibroblasts #MMPMID27835939
Zhou C; Liu F; Gallo PH; Baratz ME; Kathju S; Satish L
BMC Musculoskelet Disord 2016[]; 17 (ä): ä PMID27835939show ga
Background: Dupuytren?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-?1) 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-?1-mediated action in other fibrotic disorders. This study investigates the efficacy of PFD in vitro in inhibiting TGF-?1-mediated cellular functions leading to Dupuytren?s fibrosis. Methods: Fibroblasts harvested from (DD) and carpal tunnel (CT)- tissues were treated with or without TGF-?1 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 (?-SMA), ?2 chain of type I collagen and ?1 chain of type III collagen respectively. Results: Our results show that PFD effectively inhibits TGF-?1-induced cell migration, proliferation and cell contractile properties of both CT- and DD-derived fibroblasts. TGF-?1?induced ?-SMA mRNA and protein levels were inhibited at the higher concentration of PFD (800 ?g/ml). Interestingly, TGF-?1 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-?1-induced phosphorylation of Smad2/Smad3, a key factor in the TGF-?1 signaling pathway. Conclusion: Taken together these results suggest the PFD can potentially prevent TGF-?1?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.
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BMC+Musculoskelet+Disord 2016 ; 17 (ä): ä
