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

Cantley, M. D., Fairlie, D. P., Bartold, P. M., Rainsford, K. D., Le, G. T., Lucke, A. J., Holding, C. A. and Haynes, D. R. (2011) Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro. Journal of Cellular Physiology, 226 12: 3233-3241. doi:10.1002/jcp.22684


Author Cantley, M. D.
Fairlie, D. P.
Bartold, P. M.
Rainsford, K. D.
Le, G. T.
Lucke, A. J.
Holding, C. A.
Haynes, D. R.
Title Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro
Journal name Journal of Cellular Physiology   Check publisher's open access policy
ISSN 0021-9541
1097-4652
Publication date 2011-12
Sub-type Article (original research)
DOI 10.1002/jcp.22684
Volume 226
Issue 12
Start page 3233
End page 3241
Total pages 9
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Collection year 2012
Language eng
Formatted abstract
Histone deacetylase inhibitors (HDACi) suppress cancer cell growth, inflammation, and bone resorption. The aim of this study was to determine the effect of inhibitors of different HDAC classes on human osteoclast activity in vitro. Human osteoclasts generated from blood mononuclear cells stimulated with receptor activator of nuclear factor kappa B (RANK) ligand were treated with a novel compound targeting classes I and II HDACs (1179.4b), MS-275 (targets class I HDACs), 2664.12 (targets class II HDACs), or suberoylanilide hydroxamic acid (SAHA; targets classes I and II HDACs). Osteoclast differentiation was assessed by expression of tartrate resistant acid phosphatase and resorption of dentine. Expression of mRNA encoding for osteoclast genes including RANK, calcitonin receptor (CTR), c-Fos, tumur necrosis factor (TNF) receptor associated factor (TRAF)6, nuclear factor of activated T cells (NFATc1), interferon-β, TNF-like weak inducer of apoptosis (TWEAK), and osteoclast-associated receptor (OSCAR) were assessed. Expression of HDACs 1-10 during osteoclast development was also assessed. 1179.4b significantly reduced osteoclast activity (IC 50<0.16nM). MS-275 (IC 50 54.4nM) and 2664.12 (IC 50>100nM) were markedly less effective. A combination of MS-275 and 2664.12 inhibited osteoclast activity similar to 1179.4b (IC 50 0.35nM). SAHA was shown to suppress osteoclast activity (IC 50 12nM). 1179.4b significantly (P<0.05) reduced NFATc1, CTR, and OSCAR expression during the later stages of osteoclast development. Class I HDAC 8 and Class II HDAC5 were both elevated (P<0.05) during osteoclast development. Results suggest that inhibition of both classes I and II HDACs may be required to suppress human osteoclastic bone resorption in vitro.
Keyword Factor-Kappa-B
Time Quantitative Pcr
Postmenopausal Women
Gene-Expression
Rheumatoid-Arthritis
Receptor Activator
Differentiation
Osteoprotegerin
Rankl
Bone
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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