Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro

Cantley, Melissa; Fairlie, David P.; Bartold, P. Mark; Rainsford, K. D.; Le, Giang T.; Lucke, Andrew J.; Holding, C.A.; Haynes, David R.

doi:10.1002/jcp.22684

Cited by 65 publications

(109 citation statements)

References 55 publications

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“…4 in a number of in vitro and in vivo studies with effects on osteoclasts and osteoblasts identified [12][13][14][15][16][17][18][19][20]. HDACi have also been shown to suppress inflammation and disease progression in a number of animal models of rheumatoid arthritis (RA) [7,[21][22][23].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Since then, a number of studies have reported on suppression of osteoclastogenesis in murine cell lines and primary human osteoclasts with broad acting HDACi including TSA, FR901228 and 1179.4b [15,19,20,44,45].…”

Section: Osteoclasts Hdacs and Hdacimentioning

confidence: 99%

“…Osteoclastogenesis suppression is thought to occur through targeting of the osteoclast intercellular signalling factors following RANK/RANKL interaction, such as early activation of tumour necrosis factor (TNF) receptor associated factor-6 TRAF-6 (1179.4b) [19] and the transcription factor c-fos (TSA) [13]. HDACi (FR901228 and 1179.4b) have also been shown to induce proteosomal degradation of the NF-B-IB complex via ubiquination pathways and to directly act on key osteoclast transcription factors NF-B and nuclear factor of activated T cells (NFATc1) [15,19].…”

Section: Osteoclasts Hdacs and Hdacimentioning

confidence: 99%

“…HDACi (FR901228 and 1179.4b) have also been shown to induce proteosomal degradation of the NF-B-IB complex via ubiquination pathways and to directly act on key osteoclast transcription factors NF-B and nuclear factor of activated T cells (NFATc1) [15,19].…”

Section: Osteoclasts Hdacs and Hdacimentioning

confidence: 99%

“…For this reason, it is thought that there is redundancy between the two enzymes [34]. We and others have shown that the HDAC1-selective inhibitor MS-275 (IC 50 181 nM HDAC 1, 1160 nM HDAC 2; Table 2) suppresses osteoclast formation in a concentration dependent manner [19]. In vitro, 100 nM MS-275 significantly suppressed both the formation of tartrate resistant acid phosphatase (TRAP) positive human osteoclasts and their subsequent resorptive ability [19].…”

Section: Role Of Class I Hdacs In Osteoclast Differentiation and Bonementioning

confidence: 99%

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Histone deacetylases (HDAC) in physiological and pathological bone remodelling

Cantley

Zannettino

Bartold

et al. 2017

Bone

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Histone deacetylases (HDACs) 1 play important roles in the epigenetic regulation of gene expression in cells and are emerging therapeutic targets for treating a wide range of diseases. HDAC inhibitors (HDACi) 2 that act on multiple HDAC enzymes have been used clinically to treat a number of solid and hematological malignancies. HDACi are currently being studied also for their efficacy in nonmalignant diseases, including pathologic bone loss, but this has necessitated a better understanding of the roles of individual HDAC enzymes, particularly the eleven zinc-containing isozymes.Selective isozyme-specific inhibitors currently being developed against class I HDAC (1, 2, 3 and 8) and class II HDAC (4, 5, 6, 7, 9 and 10) will be valuable tools for elucidating the roles played by individual HDACs in different physiological and pathological settings. Isozyme-specific HDACi promise to have greater efficacy and reduced side effects, as required for treating chronic disease over extended periods of time. This article reviews the current understanding of roles for individual HDAC isozymes and effects of HDACi on bone cells, (osteoblasts, osteoclasts and osteocytes), in relation to bone remodelling in conditions characterised by pathological bone loss, including periodontitis, rheumatoid arthritis and myeloma bone disease.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Osteoclasts Hdacs and Hdacimentioning

confidence: 99%

Section: Osteoclasts Hdacs and Hdacimentioning

confidence: 99%

Section: Osteoclasts Hdacs and Hdacimentioning

confidence: 99%

Section: Role Of Class I Hdacs In Osteoclast Differentiation and Bonementioning

confidence: 99%

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Histone deacetylases (HDAC) in physiological and pathological bone remodelling

Cantley

Zannettino

Bartold

et al. 2017

Bone

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

Algate

Haynes

Fitzsimmons

et al. 2019

J of Cellular Biochemistry

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The 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.

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Azithromycin suppresses human osteoclast formation and activity in vitro

Gannon

Cantley

Haynes

et al. 2013

Journal Cellular Physiology

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Azithromycin is an antibiotic with anti‐inflammatory properties used as an adjunct to treat periodontitis, a common inflammatory mediated condition featuring pathologic alveolar bone resorption. This study aimed to determine the effect of azithromycin on human osteoclast formation and resorptive activity in vitro. Osteoclasts were generated from peripheral blood mononuclear cells stimulated with macrophage colony stimulating factor (M‐CSF) and receptor activator of nuclear factor kappa B (RANK) ligand. The effects of azithromycin at concentrations ranging from 0.5 to 40 µg/ml were tested. Osteoclast formation and activity, acidification, actin ring formation and expression of mRNA, and protein encoding for key osteoclast genes were assessed. The results demonstrated that azithromycin reduced osteoclast resorptive activity at all concentrations tested with osteoclast formation being significantly reduced at the higher concentrations (20 and 40 µg/ml). mRNA and protein expression of key osteoclast transcription factor Nuclear Factor of Activated T cells (NFATc1) was significantly reduced by azithromycin at later stages of osteoclast development (day 17). Azithromycin also reduced tumor necrosis factor receptor associated factor‐6 (TRAF6) mRNA expression at day 14, and cathepsin K mRNA expression at days 14 and 17. Integrin β3 and MMP‐9 mRNA expression was reduced by azithromycin at day 17 in osteoclasts cultured on dentine. The osteoclast proton pump did not appear to be affected by azithromycin, however formation of the actin ring cytoskeleton was inhibited. This study demonstrates that azithromycin inhibits human osteoclast function in vitro, which may account for at least some of the beneficial clinical effects observed with azithromycin treatment in periodontitis. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.

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Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro

Cited by 65 publications

References 55 publications

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

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

Azithromycin suppresses human osteoclast formation and activity in vitro

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