Elevated transforming growth factor beta and mitogen-activated protein kinase pathways mediate fibrotic traits of Dupuytren's disease fibroblasts

Background: Dupuytren'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 beta (TGF-beta) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in Dupuytren's disease. Results: We studied Dupuytren's fibroblasts in tissues ex vivo and in cells cultured in vitro and found increased TGF-beta 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-beta 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-beta expression in Dupuytren's fibroblasts, but not in control fibroblasts. Platelet-derived growth factor (PDGF) expression was strongly promoted by TGF-beta 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. Conclusions: Both TGF-beta 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.