Histone deacetylases 1 and 2 inhibition suppresses cytokine production and osteoclast bone resorption in vitro
Histone deacetylases 1 and 2 inhibition suppresses cytokine production and osteoclast bone resorption in vitro
复制标题
DOI：
10.1002/jcb.29137
复制
发表时间：
2020-01-01
影响因子：
4
通讯作者：
Cantley, Melissa
中科院分区：
文献类型：
--
作者：
Algate, Kent;Haynes, David;Cantley, Melissa
表观遗传因子的调节是多种溶骨病理中免疫功能的新兴治疗靶点。除了非组蛋白活性外，组蛋白脱乙酰酶 (HDAC) 还可以修饰核心组蛋白和转录过程。类风湿性关节炎、牙周炎和修复种植体颗粒释放中激活的免疫反应刺激破骨细胞的分解代谢活动。在这项研究中，我们研究了针对 HDAC 同工酶（HDAC 1、2 和 5）的新型治疗药物的作用，此前研究表明，在体外细胞因子刺激的人单核细胞和破骨细胞中，HDAC 同工酶在炎症性骨病中表达上调。抑制 HDAC 1 和 2 可显着降低 TNF 刺激的单核细胞中 IL-1 beta、TNF、MCP-1 和 MIP-1 alpha 的基因表达，同时抑制 IL-1 beta、IL-10、INF-gamma 和 MCP-1 的分泌 (P < .05)。通过减少 NFATc1 表达和破骨细胞特异性靶基因 TRAF6、CTR、TRAP 和组织蛋白酶 K，HDAC 1 和 2 抑制也显着减少破骨细胞形成和骨吸收 (P < .05)。当单独抑制 HDAC 1 和较小程度的 HDAC 2 时，观察到类似的趋势。然而，它们的联合抑制具有最大的抗炎和抗破骨作用。靶向 HDAC 5 对本研究中研究的这些过程的影响很小，而广泛作用的 HDACi 1179.4b 则具有广泛的抑制结果。这项研究表明，靶向 HDAC 是调节人类单核细胞和破骨细胞炎症和分解代谢过程的有效方法。它还证明了针对单个 HDAC 的重要性，总体目标是提高效率并减少任何潜在的脱靶效应。
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-1 beta, TNF, MCP-1, and MIP-1 alpha in TNF-stimulated monocytes, while suppressing secretions of IL-1 beta, IL-10, INF-gamma, 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.