title: Effective myofibroblast dedifferentiation by concomitant inhibition of TGF-β signaling and perturbation of MAPK signaling.
abstract: 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-β 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-β 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-β signaling. We have also found that a combination of chemical inhibition of TGF-β signaling and perturbation of MAPK signaling with phorbol ester mimics the anti-fibrotic effects of PDGFB, Ha-Ras(G12V) and EGR4.
authors: Laboratory of Molecular Virology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, CZ-14220 Prague 4, Czech Republic. Electronic address: kosla@img.cas.cz.
authors: Jan
authors: J
authors: Kosla
authors: Laboratory of Molecular Virology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, CZ-14220 Prague 4, Czech Republic. Electronic address: marta@img.cas.cz.
authors: Marta
authors: M
authors: Dvorakova
authors: Laboratory of Molecular Virology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, CZ-14220 Prague 4, Czech Republic. Electronic address: mdvorak@img.cas.cz.
authors: Michal
authors: M
authors: Dvorak
authors: Laboratory of Molecular Virology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, CZ-14220 Prague 4, Czech Republic. Electronic address: cermak@img.cas.cz.
authors: Vladimir
authors: V
authors: Cermak
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D054337:Cell Dedifferentiation; D002642:Chick Embryo; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000199:Actins; D010703:Phorbol Esters; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases
keywords: EGR4; FOXG1; Ha-Ras(G12V); Microarrays; Myofibroblast; PDGFB; TGF-β