Identification of Histological Patterns in Clinically Affected and Unaffected Palm Regions in Dupuytren's Disease

Dupuytren's disease is a fibro-proliferative disease characterized by a disorder of the extracellular matrix (ECM) and high myofibroblast proliferation. However, studies failed to determine if the whole palm fascia is affected by the disease. The objective of this study was to analyze several components of the extracellular matrix of three types of tissues—Dupuytren's diseased contracture cords (DDC), palmar fascia clinically unaffected by Dupuytren's disease contracture (NPF), and normal forehand fascia (NFF). Histological analysis, quantification of cells recultured from each type of tissue, mRNA microarrays and immunohistochemistry for smooth muscle actin (SMA), fibrillar ECM components and non-fibrillar ECM components were carried out. The results showed that DDC samples had abundant fibrosis with reticular fibers and few elastic fibers, high cell proliferation and myofibroblasts, laminin and glycoproteins, whereas NFF did not show any of these findings. Interestingly, NPF tissues had more cells showing myofibroblasts differentiation and more collagen and reticular fibers, laminin and glycoproteins than NFF, although at lower level than DDC, with similar elastic fibers than DDC. Immunohistochemical expression of decorin was high in DDC, whereas versican was highly expressed NFF, with no differences for aggrecan. Cluster analysis revealed that the global expression profile of NPF was very similar to DDC, and reculturing methods showed that cells corresponding to DDC tissues proliferated more actively than NPF, and NPF more actively than NFF. All these results suggest that NPF tissues may be affected, and that a modification of the therapeutic approach used for the treatment of Dupuytren's disease should be considered.This work was supported by CTS-115 (Tissue Engineering Group), University of Granada/Spain

Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target.

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