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

  • J Cell Biochem. 2020 Jan;121(1):244-258. doi: 10.1002/jcb.29137.
Kent Algate  1 ,  David Haynes  1 ,  Tracy Fitzsimmons  2 ,  Ornella Romeo  1 ,  Florence Wagner  3 ,  Edward Holson  3 ,  Robert Reid  4 ,  David Fairlie  4 ,  Peter Bartold  2 ,  Melissa Cantley  5  6
Affiliations
  • 1. Bone and Joint Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
  • 2. Faculty of Health and Medical Sciences, Adelaide Dental School, The University of Adelaide, Adelaide, South Australia, Australia.
  • 3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 4. Division of Chemistry and Structural Biology, ARC Centre of Excellence for Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • 5. Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
  • 6. Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
PMID: 31222845 DOI: 10.1002/jcb.29137
Abstract

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.

Keywords
bone loss; epigenetics; histone deacetylases (HDAC); inflammation; osteoclasts; tumor necrosis factor (TNF).
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