Effective myofibroblast dedifferentiation by concomitant inhibition of TGF-beta signaling and perturbation of MAPK signaling

0435856 - ÚMG 2015 RIV DE eng J - Článek v odborném periodiku
Kosla, Jan - Dvořáková, Marta - Dvořák, Michal - Čermák, Vladimír
Effective myofibroblast dedifferentiation by concomitant inhibition of TGF-beta signaling and perturbation of MAPK signaling.
European Journal of Cell Biology. Roč. 92, č. 12 (2013), s. 363-373. ISSN 0171-9335. E-ISSN 1618-1298
Grant CEP: GA AV ČR KAN200520801
Institucionální podpora: RVO:68378050
Klíčová slova: PDGFB * Ha-Ras(G12V) * EGR4 * TGF-beta * Myofibroblast * FOXG1 * Microarrays
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 3.699, rok: 2013

Fibrotic diseases are a group of pathologies with high incidence and mortality. Despite extensive research efforts, effective therapies are still not available. Understanding the molecular mechanisms driving the onset, progression and possible resolution of fibrosis is a prerequisite to the development of successful therapies. The central role of the TGF-beta pathway and myofibroblasts in the pathogenesis of fibrosis is now generally accepted. The possible mechanisms of myofibroblast elimination or dedifferentiation, on the other hand, are still almost uncharted territory. Here we show that sustained expression of some components of MAPK signaling pathway (PDGFB, Ha-Ras(G12V) or the transcription factor EGR4) in primary chicken embryo dermal myofibroblasts results in a loss of autocrine TGF-beta signaling and suppression of the myofibroblastic phenotype, characterized by the loss of alpha smooth muscle actin fibers and a substantial reduction in the production of extracellular matrix. Detailed analysis of the possible molecular mechanisms employed by EGR4 revealed FOXG1, BAMBI, NAB1, NAB2 and DUSP5 genes forming an EGR4 regulated network counteracting autocrine TGF-beta signaling. We have also found that a combination of chemical inhibition of TGF-beta signaling and perturbation of MAPK signaling with phorbol ester mimics the anti-fibrotic effects of PDGFB, Ha-Ras(G12V) and EGR4. (c) 2013 Elsevier GmbH. All rights reserved.
Trvalý link: http://hdl.handle.net/11104/0241975