Artikel
Concurrent inhibition of TGF- and MAP kinase pathways lead to abrogated fibrotic traits of Dupuytren’s disease fibroblasts
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Veröffentlicht: | 16. September 2010 |
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Gliederung
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Fragestellung: Which signaling pathways drive the fibro-proliferation of Dupuytren’s disease? Do chemical compounds that selectively inhibit these pathways give raise for possible non-surgical treatment strategies?
Methodik: Immunohistochemistry, Immunofluorescence, primary cell culture, reporter assay, fibroblast lattice contraction assay, mRNA and protein expression, bioinformatics based network modulation
Ergebnisse: We found that Dupuytrens’s fibroblasts in diseased tissues and cultured in vitro demonstrated increased TGF expression compared to control fibroblasts. Importantly, this correlated not only with elevated expression and activation of downstream Smad effectors, but also with overactive ERK1/2 MAP kinase signaling driven mainly through platelet-derived growth factors (PDGF). Both TGF/Smad and non-Smad signaling pathways were found to contribute to increased expression of key fibrotic markers and elevated contractility of Dupuytrens’s fibroblasts in a collagen lattice compared to control fibroblasts. Treatment with the TGF type I receptor kinase inhibitor SB-431542 and the ERK1/2 MAP kinase inhibitor PD98059 inhibited the increased contraction rate of Dupuytrens’s fibroblasts. Co-treatment of Dupuytrens’s fibroblasts with SB-431542 and PD98059 was sufficient for nearly complete inhibition of the contraction of Dupuytren’s disease fibroblasts, whereas the application of the PDGF receptor kinase inhibitor alone was not sufficient to abrogate contractility and extracellular matrix protein production. Furthermore we observed that TGF directly drives short term activation of ERK1/2 and additionally strongly promotes the expression of PDGF in Dupuytrens’s fibroblasts. Thus, we raised the question whether TGF signaling, in particular the short-term activation of ERK1/2 could lead to an autonomous non-Smad driven fibrotic stage. By modeling the TGF and PDGF network using a bioinformatics approach, we explored possible scenarios in which such a drift from Smad to autonomous non-Smad signaling can be observed.
Schlussfolgerung: All together our findings strongly suggest that usage of TGF and MAP kinase inhibitors abrogates fibrotic traits of Dupuytren’s disease which provides possible new directions for non-surgical intervention of Dupuytren’s disease.