Abstract
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.
Highlights
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
A statistically significant inhibition of both basal and Transforming growth factor-beta (TGF-β1) stimulated cell proliferation was observed at all the different concentrations, and highest inhibition was seen at 800 μg/ml
To determine the functional significance of inhibition of PFD on carpal tunnel (CT) and DD-cord derived fibroblasts, 800 μg/ml of PFD was used for further experimentation
Summary
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. Dupuytren’s disease (DD) is a common fibroproliferative disorder of the hand that is often progressive and eventually can cause contractures of the affected fingers [1]. DD is a multifactorial and complex disease, and has been reported to have an association with inherited genetic markers, alcohol and Dupuytren’s disease commonly affects populations of northern European descent, with the prevalence of DD in the general population of Western countries ranging from 0.6 to 31.6% [9]. Recurrence of DD overall ranges from 8 to 66% depending on the severity and treatment of disease [16], underscoring the importance of additional research on the causes and factors related to recurrence
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