title: Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis.
abstract: 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 beta. 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland. hossein.hemmatazad@usz.ch
authors.forename: Hossein
authors.initials: H
authors.lastname: Hemmatazad
authors.forename: Hanna Maciejewska
authors.initials: HM
authors.lastname: Rodrigues
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.forename: Fabia
authors.initials: F
authors.lastname: Brentano
authors.forename: Margarita
authors.initials: M
authors.lastname: Pileckyte
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Beat A
authors.initials: BA
authors.lastname: Michel
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Lars C
authors.initials: LC
authors.lastname: Huber
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor / Q000032:analysis; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005347:Fibroblasts / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000032:analysis; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D016133:Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000188:drug therapy*; D012867:Skin / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000627:therapeutic use
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D055513:Connective Tissue Growth Factor; C012589:trichostatin A; C543273:HDAC7 protein, human; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases