Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Arthritis Rheum. 2009 May;60(5):1519-29. doi: 10.1002/art.24494.


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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cells, Cultured
  • Collagen Type I / biosynthesis
  • Collagen Type III / biosynthesis
  • Connective Tissue Growth Factor / analysis
  • Enzyme Inhibitors / therapeutic use*
  • Extracellular Matrix Proteins / analysis
  • Fibroblasts / drug effects
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / analysis
  • Humans
  • Hydroxamic Acids / therapeutic use*
  • Intercellular Adhesion Molecule-1 / analysis
  • Polymerase Chain Reaction
  • Scleroderma, Systemic / drug therapy*
  • Skin / drug effects
  • Transforming Growth Factor beta / therapeutic use


  • Collagen Type I
  • Collagen Type III
  • Enzyme Inhibitors
  • Extracellular Matrix Proteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Transforming Growth Factor beta
  • Intercellular Adhesion Molecule-1
  • Connective Tissue Growth Factor
  • trichostatin A
  • HDAC7 protein, human
  • Hdac7 protein, mouse
  • Histone Deacetylases