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https://hdl.handle.net/2440/94584
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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 1462-0332 |
Statement of Responsibility: | 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 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1027369 |
Published version: | http://dx.doi.org/10.1093/rheumatology/kev022 |
Appears in Collections: | Aurora harvest 7 Medical Sciences publications |
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