Abstract
BackgroundDupuytren's disease is a fibroproliferative disorder of the palmar fascia. The treatment used to date has mostly been surgery, but there is a high recurrence rate. Transforming growth factor β (TGF-β) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in Dupuytren's disease.ResultsWe studied Dupuytren's fibroblasts in tissues ex vivo and in cells cultured in vitro and found increased TGF-β expression compared to control fibroblasts. This correlated not only with elevated expression and activation of downstream Smad effectors but also with overactive extracellular signal-regulated kinase 1/2 (ERK1/2)/mitogen-activated protein (MAP) kinase signalling. Treatment with the TGF-β type I receptor kinase inhibitor SB-431542 and bone morphogenetic protein 6 (BMP6) led to inhibition of elevated Smad and ERK1/2/MAP kinase signalling as well as to inhibition of the increased contractility of Dupuytren's fibroblasts. BMP6 attenuated TGF-β expression in Dupuytren's fibroblasts, but not in control fibroblasts. Platelet-derived growth factor (PDGF) expression was strongly promoted by TGF-β in Dupuytren's fibroblasts and was curbed by SB-431542 or BMP6 treatment. High basal expression of phosphorylated ERK1/2 MAP kinase and fibroproliferative markers was attenuated in Dupuytren's fibroblasts by a selective PDGF receptor kinase inhibitor. Cotreatment of Dupuytren's fibroblasts with SB-431542 and the mitogen-activated protein kinase kinase 1 inhibitor PD98059 was sufficient to abrogate proliferation and contraction of Dupuytren's fibroblasts.ConclusionsBoth TGF-β and ERK1/2 MAP kinase pathways cooperated in mediating the enhanced proliferation and high spontaneous contraction of Dupuytren's fibroblasts. Our data indicate that both signalling pathways are prime targets for the development of nonsurgical intervention strategies to treat Dupuytren's disease.
Highlights
Dupuytren’s disease is a fibroproliferative disorder of the palmar fascia
Transforming growth factor b (TGF-b)/Smad signalling upregulated in Dupuytren’s disease (DD) To evaluate the presence of TGF-b signalling in DD, nodules from the palmar fascia of four DD patients were surgically removed and compared to normal palmar fascia from four control patients who had undergone carpal tunnel release surgery (Table 1)
Previous studies had shown an increase in TGF-b1 levels in DD; we extended these studies by examining TGF-b3, and examined P-Smad2 as a measure for active canonical TGF-b signalling and a-smooth muscle actin (a-SMA) as a marker for myofibroblasts
Summary
The treatment used to date has mostly been surgery, but there is a high recurrence rate. Transforming growth factor b (TGF-b) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in Dupuytren’s disease. Patients commonly first display a nodule in the palm or on the volar (palmar) aspect of the fingers caused by a thickened layer of tissue (palmar fascia) between the skin and the tendons of the hand and fingers. Because of high recurrence rates following surgery, investigations are underway to determine the underlying causes of DD to optimise treatment strategies [1,2]. Many growth factors have been implicated in Dupuytren’s contracture; transforming growth factor b (TGF-b) in particular has been proposed to play a prominent role [6]
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