Trichostatin A inhibits osteoclastogenesis and bone resorption by suppressing the induction of c-Fos by RANKL

Histone deacetylases are enzymes involved in the remodeling of chromatin Structure. ill the regulation of transcriptional activity, and in epigenetic integrity. Histone deacetylase inhibitors Such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) have emerged as potent anticancer drugs that have proved useful in preclinical and early clinical trials. The role of historic deacetylase inhibitors in regulating osteoclast differentiation, however, is not well established. Ill this Study, we analyzed the effects of TSA oil osteoclast differentiation induced by the differentiation factor RANKL (receptor activator of NF-kappa B ligand). TSA strongly inhibited osteoclast formation in coculture of bone marrow cells and osteoblasts without reducing RANKL expression in osteoblasts. Furthermore, TSA suppressed RANKL-induced osteoclast formation from primary bone marrow-derived macrophages. TSA was only effective when present during the early stage of osteoclast differentiation. This effect was accompanied by a significant decrease in the RANKL-stimulated induction of c-Fos and NFATc1, which are key transcription factors during early osteoclastogenesis. The ectopic introduction of c-Fos and a constitutively active form of NFATc1 reversed the TSA-induccd antiosteoclastogenic effect. Consistent with the in vitro results, TSA inhibited lipopolysaccharide- and interleukin-1-induced bone resorption and osteoclast formation in all in vivo model. Taken together, our findings suggest a novel action of TSA: inhibiting RANKL-induced osteoclast formation by suppressing the induction of the osteoclastogenic transcription factor c-Fos. Also, the inhibitory effect of TSA oil bone destruction ill Vivo Suggests that histone deacetylase inhibitors may be novel therapeutics for treating typical bone diseases. (C) 2009 Elsevier B.V. All rights reserved.