Inhibitors of Histone Deacetylases in Class I and Class II Suppress Human Osteoclasts In Vitro
Inhibitors of Histone Deacetylases in Class I and Class II Suppress Human Osteoclasts In Vitro
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DOI：
10.1002/jcp.22684
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发表时间：
2011-12-01
影响因子：
5.6
通讯作者：
Haynes, D. R.
中科院分区：
文献类型：
--
作者：
Cantley, M. D.;Fairlie, D. P.;Haynes, D. R.
组蛋白去乙酰化酶抑制剂（HDACi）抑制癌细胞生长、炎症和骨吸收。本研究的目的是确定不同类型的HDAC抑制剂对体外人破骨细胞活性的影响。通过核因子κ B受体激活剂（RANK）配体刺激血单个核细胞生成的人破骨细胞，用一种靶向I类和II类hdac的新型化合物（1177.4 B）、MS-275（靶向I类hdac）、2664.12（靶向II类hdac）或亚甲基苯胺羟肟酸（SAHA，靶向I类和II类hdac）处理。通过抗酒石酸酸性磷酸酶的表达和牙本质的再吸收来评估破骨细胞的分化。评估编码破骨细胞基因的mRNA表达，包括RANK、降钙素受体（CTR）、c-Fos、肿瘤坏死因子（TNF）受体相关因子（TRAF） 6、活化T细胞核因子（NFATc1）、干扰素- β、TNF样细胞凋亡弱诱导剂（TWEAK）和破骨细胞相关受体（OSCAR）。同时评估破骨细胞发育过程中HDACs 1-10的表达。1179.4b显著降低破骨细胞活性（IC50 < 0.16 nM）。MS-275 （IC50 54.4 nM）和2664.12 （IC50 > 100 nM）的效果明显差。MS-275和2664.12联合抑制破骨细胞活性与1179.4b相似（IC50 0.35 nM）。SAHA抑制破骨细胞活性（IC50 12 nM）。1179.4b在破骨细胞发育后期显著（P < 0.05）降低了NFATc1、CTR和OSCAR的表达。I类HDAC 8和II类HDAC5在破骨细胞发育过程中均升高（P < 0.05）。结果表明，抑制I类和II类hdac可能需要体外抑制人破骨细胞骨吸收。j .细胞。中国生物医学工程学报，2011,31(2):393 - 394。(C) 2011 Wiley期刊公司
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-beta, 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 (IC50 < 0.16 nM). MS-275 (IC50 54.4 nM) and 2664.12 (IC50 > 100 nM) were markedly less effective. A combination of MS-275 and 2664.12 inhibited osteoclast activity similar to 1179.4b (IC50 0.35 nM). SAHA was shown to suppress osteoclast activity (IC50 12 nM). 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. J. Cell. Physiol. 226: 3233-3241, 2011. (C) 2011 Wiley Periodicals, Inc.