Open AccessHistone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis
Author(s) -
Hemmatazad Hossein,
Rodrigues Hanna Maciejewska,
Maurer Britta,
Brentano Fabia,
Pileckyte Margarita,
Distler Jörg H. W.,
Gay Renate E.,
Michel Beat A.,
Gay Steffen,
Huber Lars C.,
Distler Oliver,
Jüngel Astrid
Publication year - 2009
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.24494
Subject(s) - trichostatin a , ctgf , fibronectin , histone deacetylase , gene silencing , extracellular matrix , chemistry , fibrosis , cancer research , growth factor , microbiology and biotechnology , small interfering rna , histone , biology , medicine , rna , biochemistry , receptor , gene
Objective We have recently shown a significant reduction in cytokine‐induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC‐7) as a possible mechanism by which TSA exerts its antifibrotic function. Methods Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor β. Expression of HDACs 1–11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM‐1) was analyzed by real‐time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC‐7 was silenced using small interfering RNA. Results SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC‐7, whereas HDAC‐3 was up‐regulated. Silencing of HDAC‐7 decreased the constitutive and cytokine‐induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM‐1, while silencing of HDAC‐7 had no effect on their expression. Conclusion Silencing of HDAC‐7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up‐regulate the expression of profibrotic molecules such as ICAM‐1 and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc.