Trichostatin A Inhibits Osteoclastogenesis and Bone Resorption by Suppressing the Induction of c-Fos by RANKL

Eur J Pharmacol. 2009 Nov 25;623(1-3):22-9. doi: 10.1016/j.ejphar.2009.09.025. Epub 2009 Sep 17.

Abstract

Histone deacetylases are enzymes involved in the remodeling of chromatin structure, in 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 histone deacetylase inhibitors in regulating osteoclast differentiation, however, is not well established. In this study, we analyzed the effects of TSA on osteoclast differentiation induced by the differentiation factor RANKL (receptor activator of NF-kappaB 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-induced antiosteoclastogenic effect. Consistent with the in vitro results, TSA inhibited lipopolysaccharide- and interleukin-1-induced bone resorption and osteoclast formation in an 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 on bone destruction in vivo suggests that histone deacetylase inhibitors may be novel therapeutics for treating typical bone diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Neoplasms / drug therapy
  • Bone Resorption / chemically induced
  • Bone Resorption / drug therapy*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Hydroxamic Acids / metabolism
  • Hydroxamic Acids / pharmacology*
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Mice
  • Mice, Inbred ICR
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Osteitis / drug therapy
  • Osteoblasts / metabolism
  • Osteoclasts / drug effects*
  • Osteoclasts / physiology
  • Osteoprotegerin / genetics
  • Osteoprotegerin / metabolism
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / metabolism
  • RANK Ligand / genetics
  • RANK Ligand / metabolism*
  • Skull / cytology

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Interleukin-1
  • Lipopolysaccharides
  • NFATC Transcription Factors
  • Osteoprotegerin
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • trichostatin A