HDAC inhibitor, trichostatin A suppresses osteoclastogenesis by up-regulating the expression of C/EBP-β and MKP-1

Histone deacetylases (HDACs) remove the acetyl groups from the lysine residues of histone tails, leading to the formation of a condensed and transcriptionally silenced chromatin. HDAC inhibitors (HDACi) block this action and can result in hyperacetylation of histones, leading to a less compact and more transcriptionally active chromatin and thereby, gene expression. Previously, we have shown that HDACi inhibit osteoclast differentiation. However, which genes are transcriptionally activated following hyperacetylation of histones, and lead to the suppression of osteoclastogenesis, has yet to be elucidated. In this study, we show that a HDACi, trichostatin A (TSA), inhibits receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) stimulated TNF-α production, NF-κB activation and bone resorbing pit formation and down-regulates cFos and NFATc1 in RAW264.7 cells. Interestingly, anti-osteoclastogenic factors CCAAT enhancer binding protein (C/EBP)-β and mitogen activated protein kinase phosphatase (MKP)-1 expression were significantly up-regulated in TSA-treated RANKL-stimulated RAW264.7 cells. These findings suggest that TSA up-regulates the expression of C/EBP-β and MKP-1 which may down-regulate pro-osteoclastogenic factors and signaling molecules, ultimately suppressing osteoclastogenesis.