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

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