Histone deacetylases 1 and 2 inhibition suppresses cytokine production and osteoclast bone resorption in vitro

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dc.contributor.authorAlgate, K.
dc.contributor.authorHaynes, D.
dc.contributor.authorFitzsimmons, T.
dc.contributor.authorRomeo, O.
dc.contributor.authorWagner, F.
dc.contributor.authorHolson, E.
dc.contributor.authorReid, R.
dc.contributor.authorFairlie, D.
dc.contributor.authorBartold, P.
dc.contributor.authorCantley, M.
dc.date.issued2020
dc.descriptionFirst published: 21 June 2019
dc.description.abstractThe regulation of epigenetic factors is an emerging therapeutic target of immune function in a variety of osteolytic pathologies. Histone deacetylases (HDAC) modify core histone proteins and transcriptional processes, in addition to nonhistone protein activity. The activated immune response in rheumatoid arthritis, periodontitis, and prosthetic implant particle release stimulates the catabolic activity of osteoclasts. In this study, we investigated the effects of novel therapeutic agents targeting HDAC isozymes (HDAC 1, 2, and 5), previously shown to be upregulated in inflammatory bone disorders, in cytokine-stimulated human monocytes and osteoclasts in vitro. Inhibiting HDAC 1 and 2 significantly reduced gene expression of IL-1β, TNF, MCP-1, and MIP-1α in TNF-stimulated monocytes, while suppressing secretions of IL-1β, IL-10, INF-γ, and MCP-1 (P < .05). Osteoclast formation and bone resorption were also significantly diminished with HDAC 1 and 2 inhibition, through reduced NFATc1 expression and osteoclast specific target genes, TRAF6, CTR, TRAP, and Cathepsin K (P < .05). Similar trends were observed when inhibiting HDAC 1 and to a lesser extent, HDAC 2, in isolation. However, their combined inhibition had the greatest anti-inflammatory and antiosteoclastic effects. Targeting HDAC 5 had minimal effects on these processes investigated in this study, whereas a broad acting HDACi, 1179.4b, had widespread suppressive outcomes. This study demonstrates that targeting HDACs is a potent and effective way of regulating the inflammatory and catabolic processes in human monocytes and osteoclasts. It also demonstrates the importance of targeting individual HDACs with an overall aim to improve efficiency and reduce any potential off target effects.
dc.description.statementofresponsibilityKent Algate, David Haynes, Tracy Fitzsimmons, Ornella Romeo, Florence Wagner, Edward Holson, Robert Reid, David Fairlie, Peter Bartold, Melissa Cantley
dc.identifier.citationJournal of Cellular Biochemistry, 2020; 121(1):244-258
dc.identifier.doi10.1002/jcb.29137
dc.identifier.issn0730-2312
dc.identifier.issn1097-4644
dc.identifier.orcidAlgate, K. [0000-0002-0224-5322]
dc.identifier.orcidFitzsimmons, T. [0000-0002-1029-8352]
dc.identifier.orcidRomeo, O. [0000-0001-7088-7266]
dc.identifier.orcidBartold, P. [0000-0002-5695-3877] [0000-0002-6225-3084]
dc.identifier.orcidCantley, M. [0000-0002-7188-0928]
dc.identifier.urihttp://hdl.handle.net/2440/119902
dc.language.isoen
dc.publisherWiley
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1070880
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1057835
dc.rights© 2019 Wiley Periodicals, Inc.
dc.source.urihttps://doi.org/10.1002/jcb.29137
dc.subjectbone loss
dc.subjectepigenetics
dc.subjecthistone deacetylases (HDAC)
dc.subjectinflammation
dc.subjectosteoclasts
dc.subjecttumor necrosis factor (TNF)
dc.titleHistone deacetylases 1 and 2 inhibition suppresses cytokine production and osteoclast bone resorption in vitro
dc.typeJournal article
pubs.publication-statusPublished

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