Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target.
Verjee LS., Verhoekx JSN., Chan JKK., Krausgruber T., Nicolaidou V., Izadi D., Davidson D., Feldmann M., Midwood KS., Nanchahal J.
Dupuytren's disease is a very common progressive fibrosis of the palm leading to flexion deformities of the digits that impair hand function. The cell responsible for development of the disease is the myofibroblast. There is currently no treatment for early disease or for preventing recurrence following surgical excision of affected tissue in advanced disease. Therefore, we sought to unravel the signaling pathways leading to the development of myofibroblasts in Dupuytren's disease. We characterized the cells present in Dupuytren's tissue and found significant numbers of immune cells, including classically activated macrophages. High levels of proinflammatory cytokines were also detected in tissue from Dupuytren's patients. We compared the effects of these cytokines on contraction and profibrotic signaling pathways in fibroblasts from the palmar and nonpalmar dermis of Dupuytren's patients and palmar fibroblasts from non-Dupuytren's patients. Exogenous addition of TNF, but not other cytokines, including IL-6 and IL-1β, promoted differentiation into specifically of palmar dermal fibroblasts from Dupuytren's patients in to myofibroblasts. We also demonstrated that TNF acts via the Wnt signaling pathway to drive contraction and profibrotic signaling in these cells. Finally, we examined the effects of targeted cytokine inhibition. Neutralizing antibodies to TNF inhibited the contractile activity of myofibroblasts derived from Dupuytren's patients, reduced their expression of α-smooth muscle actin, and mediated disassembly of the contractile apparatus. Therefore, we showed that localized inflammation in Dupuytren's disease contributes to the development and progression of this fibroproliferative disorder and identified TNF as a therapeutic target to down-regulate myofibroblast differentiation and activity.