HDAC and HDACi: pathogenetic and mechanistic insights (original) (raw)

Rheumatoid arthritis

Nature Reviews Rheumatology volume 7, page 682 (2011)Cite this article

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Epigentic mechanisms help to regulate proinflammatory cytokine production and, thus, might be important in the pathogenesis of rheumatoid arthritis (RA). Histone deacetylases (HDACs) remove acetyl groups from lysine residues of histones, resulting in chromatin condensation and repression of transcription; as key players in the control of chromatin dynamics they could be a novel therapeutic target in RA. Despite extensive research, many questions remain unanswered regarding the role of HDAC in RA pathogenesis, whether HDAC inhibitors (HDACi) could really work in this disease, and the mechanisms of action of these agents. Two new papers add to our knowledge of this interesting area of research.

The authors also tested the effects of two HDACi on cytokine production: trichostatin A (TSA), a nonselective HDACi, and MI192, a new HDAC3-selective inhibitor developed by Ron Grigg. MI192 showed a dose-dependent inhibition of IL-6 in RA PBMC but not in healthy PBMC, whereas TSA was a potent inhibitor of IL-6 production by both cell types.

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ORIGINAL RESEARCH PAPERS

  1. Gillepsie, J. et al. Histone deacetylases are dysregulated in rheumatoid arthritis and a novel HDAC3-selective inhibitor reduces IL-6 production by PBMC of RA patients. Arthritis Rheum. doi:10.1002/art.33382
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  2. Grabiec, A. M. et al. Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann. Rheum. Dis. doi:10.1136/ard.2011.154211
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Buckland, J. HDAC and HDACi: pathogenetic and mechanistic insights.Nat Rev Rheumatol 7, 682 (2011). https://doi.org/10.1038/nrrheum.2011.162

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