title: MS-275, a benzamide histone deacetylase inhibitor, prevents osteoclastogenesis by down-regulating c-Fos expression and suppresses bone loss in mice.
abstract: Histone deacetylase (HDAC) enzymes play important roles in physiological and pathological processes by catalyzing the deacetylation of lysine residues in histone and non-histone proteins. Inhibition of HDACs has emerged as an attractive therapeutic strategy for various diseases including cancer and inflammatory diseases. We recently found that MS-275, a class I-specific HDAC inhibitor, exhibits an anabolic effect on bone through promoting expression of alkaline phosphatase in osteoblasts. MS-275 has also been suggested to inhibit inflammatory bone destruction, but the underlying mechanisms are still poorly understood. In this study, we investigated the effects and mechanism of action of MS-275 on osteoclast differentiation and activation. We found that MS-275 inhibits osteoclast differentiation in coculture of osteoblasts and bone marrow cells without affecting expression of receptor activator of NF-κB ligand (RANKL), a key cytokine for osteoclast differentiation, in osteoblasts. MS-275 inhibited RANKL-mediated osteoclast differentiation from its precursors by suppressing RANKL-induced expression of c-Fos, a crucial transcription factor for osteoclastogenesis. The inhibitory effect of MS-275 on osteoclast differentiation was blunted by ectopic overexpression of c-Fos. In addition to osteoclast differentiation, MS-275 decreased bone resorbing activity of mature osteoclasts. Consistent with the in vitro effects, MS-275 decreased osteoclast number and bone destruction in IL-1-induced mouse calvarial bone destruction model. Taken together, our results demonstrate that MS-275 suppresses bone destruction by inhibiting osteoclast differentiation and activation, suggesting a potential therapeutic value of MS-275 for bone disorders associated with increased bone resorption.
authors: Department of Cell and Developmental Biology, DRI, School of Dentistry, Seoul National University, 28 Yeongon-Dong, Jongno-Gu, Seoul 110-749, Republic of Korea.
authors: Ha-Neui
authors: HN
authors: Kim
authors: Jong-Ho
authors: JH
authors: Lee
authors: Won Jong
authors: WJ
authors: Jin
authors: Sungjin
authors: S
authors: Ko
authors: Kyoungsuk
authors: K
authors: Jung
authors: Hyunil
authors: H
authors: Ha
authors: Zang Hee
authors: ZH
authors: Lee
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D053245:RANK Ligand / Q000235:genetics
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D007375:Interleukin-1; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D053245:RANK Ligand; C118739:entinostat