{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:56:56Z","timestamp":1791291416779,"version":"4.3.0"},"reference-count":33,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2007,7,30]],"date-time":"2007-07-30T00:00:00Z","timestamp":1185753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2007,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Tissue fibrosis is a hallmark compromising feature of many disorders. In this study, we investigated the antifibrogenic effects of the histone deacetylase inhibitor trichostatin A (TSA) on cytokine\u2010driven fibrotic responses in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Skin fibroblasts from patients with systemic sclerosis (SSc) and normal healthy control subjects were stimulated with profibrotic cytokines in combination with TSA. Human Col\u03b11(I) and fibronectin were measured using real\u2010time polymerase chain reaction, and levels of soluble collagen were estimated using the SirCol collagen assay. Electromobilty shift assay and confocal fluorescence microscopy were used to investigate the intracellular distribution of Smad transcription factors. For in vivo analysis, skin fibrosis was quantified by histologic assessment of mouse skin tissue in a model of bleomycin\u2010induced fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Reductions in the cytokine\u2010induced transcription of Col\u03b11(I) and fibronectin were observed in both normal and SSc skin fibroblasts following the addition of TSA. Similarly, the expression of total collagen protein in TSA\u2010stimulated SSc skin fibroblasts was reduced to basal levels. The mechanism of action of TSA included inhibition of the nuclear translocation and DNA binding of profibrotic Smad transcription factors. Western blot analysis revealed an up\u2010regulation of the cell cycle inhibitor p21 by TSA, leading to reduced proliferation of fibroblasts. In addition, in bleomycin\u2010induced fibrosis in mice, TSA prevented dermal accumulation of extracellular matrix in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings provide novel insights into the epigenetic regulation of fibrosis. TSA and similar inhibitory compounds appear to represent early therapeutic strategies for achieving reversal of the cytokine\u2010driven induction of matrix synthesis that leads to fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.22759","type":"journal-article","created":{"date-parts":[[2007,7,30]],"date-time":"2007-07-30T16:18:48Z","timestamp":1185812328000},"page":"2755-2764","source":"Crossref","is-referenced-by-count":146,"title":["Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin\u2010induced skin fibrosis"],"prefix":"10.1002","volume":"56","author":[{"given":"Lars C.","family":"Huber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg H. 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