Dupuytren's Disease Is Mediated by Insufficient TGF-β1 Release and Degradation

Dupuytren's disease (DD) is a fibroproliferative disorder affecting the palmar fascia, causing functional restrictions of the hand and thereby limiting patients' daily lives. The disturbed and excessive myofibroblastogenesis, causing DD, is mainly induced by transforming growth factor (TGF)-beta 1. But, the extent to which impaired TGF-beta 1 release or TGF-beta signal degradation is involved in pathologically altered myofibroblastogenesis in DD has been barely examined. Therefore, the complex in which TGF-beta 1 is secreted in the extracellular matrix to elicit its biological activity, and proteins such as plasmin, integrins, and matrix metalloproteinases (MMPs), which are involved in the TGF-beta 1 activation, were herein analyzed in DD-fibroblasts (DD-FBs). Additionally, TGF-beta signal degradation via caveolin-1 was examined with 5-fluoruracil (5-FU) in detail. Gene expression analysis was performed via Western blot, PCR, and immunofluorescence analyses. As a surrogate parameter for disturbed myofibroblastogenesis, alpha-smooth-muscle-actin (alpha-SMA) expression was evaluated. It was demonstrated that latency-associated peptide (LAP)-TGF-beta and latent TGF-beta-binding protein (LTBP)-1 involved in TGF-beta-complex building were significantly upregulated in DD. Plasmin a serinprotease responsible for the TGF-beta release was significantly downregulated. The application of exogenous plasmin was able to inhibit disturbed myofibroblastogenesis, as measured via alpha-SMA expression. Furthermore, a reduced TGF-beta 1 degradation was also involved in the pathological phenotype of DD, because caveolin-1 expression was significantly downregulated, and if rescued, myofibroblastogenesis was also inhibited. Therefore, our study demonstrates that a deficient release and degradation of TGF-beta 1 are important players in the pathological phenotype of DD and should be addressed in future research studies to improve DD therapy or other related fibrotic conditions.