Histone deacetylase inhibitor MS‐275 stimulates bone formation in part by enhancing Dhx36‐mediated TNAP transcription

组蛋白脱乙酰基酶 抄写(语言学) 化学 组蛋白脱乙酰酶抑制剂 药理学 癌症研究 细胞生物学 组蛋白 HDAC11型 医学 生物 生物化学 DNA 哲学 语言学
作者
Ha‐Neui Kim,Jong-Ho Lee,Suk‐Chul Bae,Hyun‐Mo Ryoo,Hong-Hee Kim,Hyunil Ha,Zang Hee Lee
出处
期刊:Journal of Bone and Mineral Research [Wiley]
卷期号:26 (9): 2161-2173 被引量:51
标识
DOI:10.1002/jbmr.426
摘要

Abstract Histone deacetylases (HDACs) deacetylate both histones and nonhistone proteins and play a key role in the regulation of physiologic and aberrant gene expression. Inhibition of HDACs has emerged as a promising therapeutic target for cancer and neurologic diseases. In this study we investigated the osteogenic effect and mechanism of action of MS-275, a class I HDAC inhibitor with preference for HDAC1. Both local and systemic administration of MS-275 stimulated bone regeneration in animal models. MS-275 stimulated mRNA expression and activity of the early osteogenic marker tissue-nonspecific alkaline phosphatase (TNAP) in bone tissue and osteogenic cells. By using a series of TNAP promoter deletion constructs and a DNA affinity precipitation assay, we identified DExH-box helicase Dhx36 as a factor that binds to the MS-275 response element in the TNAP promoter. We also found that Dhx36 binding to the MS-275 response element is crucial for MS-275 induction of TNAP transcription. Dhx36 physically interacted with a subset of HDACs (HDAC1 and -4) whose protein levels were downregulated by MS-275, and forced expression of these HDACs blunted the stimulatory effects of MS-275 by a deacetylase activity–independent mechanism(s). Taken together, the results of our study show that MS-275 induces TNAP transcription by decreasing the interaction of HDAC1/4 with Dhx36, which can at least in part contribute to the bone anabolic effects of MS-275. © 2011 American Society for Bone and Mineral Research
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