Histone deacetylases induce osteoclastogenesis by regulation of AP‐1 and Erk pathways

Abstract

The acetylation state of histones is controlled by two classes of enzymes, histone deacetylases (HDACs) and histone acetyl transferases (HATs). Histone deacetylase inhibitors (HDIs) such as trichostatin A (TSA) and sodium butyrate (NaB) are using as potentially useful components of the anti-cancer agents with low toxicity. Osteoclasts are multinucleated cells with bone resorbing activity and its proliferation and differentiation are supported through the presence of receptor activator of NF-κB ligand (RANKL) and M-CSF by the activation of osteoblasts, bone forming cells. In this study, we analyzed the effect of TSA and NaB, two specific HDIs, on osteoclast differentiation in vitro. Inhibition of histone deacetylase by HDIs suppresses osteoclast differentiation of osteoclast precursors. Especially, TSA inhibits the expression of c-fos and NFATc1, two essential molecules for osteoclastogenesis, and the kinase activity of phosphorylated Erk. Also, the introduction of c-fos and NFATc1 retrovirus to osteoclast precursors leads to TRAP-positive osteoclast differentiation in the presence of HDIs. To elucidate the in vivo effects of TSA on osteoclastogenesis, we treated LPS-induced bone loss mouse model with TSA(1mg/kg/d) for 7days. Compared with vehicle-treated control mice, TSA-treated mice exhibited a significant reduction in LPS-induced bone loss. Taken together, these findings suggest that inhibition of HDAC suppresses osteoclastogenesis and bone destruction by the novel pathways to mediate the expression c-fos and NFATc1 as well as Erk.