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.

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.

• Authors: Hossein Hemmatazad, Hanna Maciejewska Rodrigues, Britta Maurer, Fabia Brentano, Margarita Pileckyte, Jörg H W Distler, Renate E Gay, Beat A Michel, Steffen Gay, Lars C Huber, Oliver Distler, Astrid Jüngel
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 5 Pg. 1519-29 (May 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19404935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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)