title: Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-beta production.
abstract: Osteoclasts are bone-resorptive multinucleated cells that are differentiated from hemopoietic cell lineages of monocyte/macrophages in the presence of receptor activator of NF-kappaB ligand (RANKL) and M-CSF. Downstream signaling molecules of the receptor of RANKL, RANK, modulate the differentiation and the activation of osteoclasts. We recently found that histone deacetylase inhibitors (HDIs), known as anticancer agents, selectively suppressed osteoclastogenesis in vitro. However, the molecular mechanism underlying inhibitory action of HDIs in osteoclastogenesis and the effect of HDIs on pathological bone destruction are still not remained to be elucidated. In this study, we show that a depsipeptide, FR901228, inhibited osteoclast differentiation by not only suppressing RANKL-induced nuclear translocation of NFATc1 but also increasing the mRNA level of IFN-beta, an inhibitor of osteoclastogenesis. The inhibition of osteoclast formation by FR901228 was abrogated by the addition of IFN-beta-neutralizing Ab. In addition, treatment of adjuvant-induced arthritis in rats revealed that FR901228 inhibited not only disease development in a prophylactic model but also bone destruction in a therapeutic model. Furthermore, immunostaining of the joints of therapeutically treated rats revealed significant production of IFN-beta in synovial cells. Taken together, these data suggest that a HDI inhibits osteoclastogenesis and bone destruction by a novel action to induce the expression of osteoclast inhibitory protein, IFN-beta.
authors.affiliation: Department of Pathology and Biodefense, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toshio
authors.initials: T
authors.lastname: Kukita
authors.forename: Takeo
authors.initials: T
authors.lastname: Shobuike
authors.forename: Kengo
authors.initials: K
authors.lastname: Nagata
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wu
authors.forename: Kenji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takao
authors.initials: T
authors.lastname: Hotokebuchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Kohashi
authors.forename: Akiko
authors.initials: A
authors.lastname: Kukita
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control; D001862:Bone Resorption / Q000517:prevention & control*; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D016899:Interferon-beta / Q000096:biosynthesis*; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D053245:RANK Ligand; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002352:Carrier Proteins; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D016899:Interferon-beta; C087123:romidepsin