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Type: Journal article
Title: Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis
Author: Cantley, M.
Fairlie, D.
Bartold, P.
Marino, V.
Gupta, P.
Haynes, D.
Citation: Rheumatology, 2015; 54(9):1713-1723
Publisher: Oxford University Press
Issue Date: 2015
ISSN: 1462-0324
Statement of
Melissa D. Cantley, David P. Fairlie, P. Mark Bartold, Victor Marino, Praveer K. Gupta, and David R. Haynes
Abstract: OBJECTIVE: Histone deacetylase 1 (HDAC1) is highly expressed in the synovium of RA patients. Thus we aimed to investigate a novel HDAC inhibitor (HDACi), NW-21, designed to target HDAC1. The effect of NW-21 on osteoclast formation and activity, cytokine and chemokine expression in vitro and arthritis in mice was assessed. METHODS: The effects on human osteoclast formation and activity derived from human blood monocytes stimulated with receptor activator of nuclear factor κB ligand (RANKL) and M-CSF were assessed. The anti-inflammatory activity of NW-21 was assessed using human monocytes stimulated with either TNF-α or lipopolysaccharide for 24 h. mRNA expression of monocyte chemotactic protein 1 (MCP-1), TNF-α, macrophage inflammatory protein 1α (MIP-1α), IL-1 and RANTES (regulated on activation, normal T cell expressed and secreted) was assessed. The effect of NW-21 in the collagen antibody-induced arthritis model was assessed following daily oral administration at 5 mg/kg/day. The HDAC1 inhibitors NW-21 and MS-275 were compared with a broad-acting HDACi, 1179.4b. Effects on inflammation and bone were assessed using paw inflammation scoring, histology and live animal micro-CT. RESULTS: NW-21 suppressed osteoclast formation and activity as well as significantly reducing mRNA expression of MCP-1 and MIP-1α in monocytes stimulated by lipopolysaccharide or TNF-α (P < 0.05) in vitro. Only inhibitors that targeted HDAC1 (NW-21 and MS-275) reduced inflammation and bone loss in the arthritis model. CONCLUSION: The results indicate that inhibitors targeting HDAC1, such as NW-21 and MS-275, may be useful for treating RA, as such drugs can simultaneously target both inflammation and bone resorption.
Keywords: Histone deacetylase 1; inflammation; osteoclasts; bone loss; collagen antibody-induced arthritis
Rights: © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.
DOI: 10.1093/rheumatology/kev022
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