title: Trichostatin A, a histone deacetylase inhibitor, suppresses collagen synthesis and prevents TGF-beta(1)-induced fibrogenesis in skin fibroblasts.
abstract: Excessive production of collagens by alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts leads to fibrotic skin diseases, such as hypertrophic scarring. This process is characterized by an imbalance between extracellular matrix (ECM) synthesis and degradation, while transforming growth factor beta (TGF-beta(1)), known to be a key mediator of fibrogenesis, is up-regulated. In this study we have investigated the possible antifibrogenic effect of Trichostatin A (TSA), a histone deacetylase inhibitor, on rat skin fibroblasts in culture. mRNA steady-state levels and de novo protein synthesis of procollagen types I and III and alpha-SMA were inhibited when skin fibroblasts were treated with 100 nM TSA with or without TGF-beta(1). While the transcription rate of the procollagen alpha1(I) gene was increased following TSA or TGF-beta(1) treatment, TSA abrogated the stimulatory effect of TGF-beta(1) on procollagen alpha1(I) transcription when both compounds were added simultaneously. The reduction of procollagen alpha1(I) and alpha1(III) mRNA steady-state levels by TSA did not require de novo protein synthesis, while the effect of TSA on alpha-SMA mRNA steady-state levels was cycloheximide-sensitive. Interestingly, TSA affected TGF-beta(1) and its downstream mediators, i.e., the Smad family proteins. TSA strongly induced in a biphasic way the expression of 5'TG3' interacting factor (TGIF), a known endogenous corepressor molecule of the TGF-beta(1) signaling pathway. Addition of exogenous TGF-beta(1) did not interfere with the effect of TSA on the TGIF mRNA level. Our study shows that inhibition of histone deacetylases by TSA reduces expression of fibrosis-related genes in skin fibroblasts and this coincides by alterations in the TGF-beta(1) signaling pathway.
authors.affiliation: Laboratory for Molecular Liver Cell Biology, Faculty of Medicine and Pharmacy, Free University of Brussels, Laarbeeklaan 103, 1090 Brussels-Jette, Belgium. krom@cyto.vub.ac.be
authors.forename: Krista
authors.initials: K
authors.lastname: Rombouts
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.forename: Patricia
authors.initials: P
authors.lastname: Greenwel
authors.forename: Alain
authors.initials: A
authors.lastname: Vandermonde
authors.forename: Annemie
authors.initials: A
authors.lastname: Wielant
authors.forename: Karine
authors.initials: K
authors.lastname: Hellemans
authors.forename: Pieter
authors.initials: P
authors.lastname: De Bleser
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Marcos
authors.initials: M
authors.lastname: Rojkind
authors.forename: Albert
authors.initials: A
authors.lastname: Geerts
mesh_terms: D000818:Animals; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004336:Drug Antagonism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000517:prevention & control*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011500:Protein Synthesis Inhibitors; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C012589:trichostatin A; D003094:Collagen