title: HDAC inhibitor trichostatin A suppresses osteoclastogenesis by upregulating the expression of C/EBP-β and MKP-1.
abstract: 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 an HDACi, trichostatin A (TSA), inhibits the receptor activator of the nuclear factor-κB (NF-κB) ligand (RANKL)-stimulated TNF-α production, NF-κB activation, and bone resorbing pit formation, and downregulates c-Fos and NFATc1 in RAW 264.7 cells. Interestingly, expression of antiosteoclastogenic factors CCAAT enhancer binding protein (C/EBP)-β and mitogen-activated protein kinase phosphatase (MKP)-1 was significantly upregulated in TSA-treated, RANKL-stimulated RAW 264.7 cells. These findings suggest that TSA upregulates the expression of C/EBP-β and MKP-1, which may downregulate pro-osteoclastogenic factors and signaling molecules, ultimately suppressing osteoclastogenesis.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Williams
authors.forename: Kazi
authors.initials: K
authors.lastname: Nishu
authors.forename: Md Mizanur
authors.initials: MM
authors.lastname: Rahman
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C012589:trichostatin A; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse