Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages

Mizanur Rahman, Akiko Kukita, Toshio Kukita, Takeo Shobuike, Takahiro Nakamura, Osamu Kohashi

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Histone deacetylase (HDAC) inhibitors are emerging as a new class of anticancer therapeutic agents and have been demonstrated to induce differentiation in some myeloid leukemia cell lines. In this study, we show that HDAC inhibitors have a novel action on osteoclast differentiation. The effect of 2 HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on osteoclastogenesis was investigated using rat and mouse bone marrow cultures and a murine macrophage cell line RAW264. Both TSA and NaB inhibited the formation of preosteoclast-like cells (POCs) and multinucleated osteoclast-like cells (MNCs) in rat bone marrow culture. By reverse transcription-polymerase chain reaction analysis, TSA reduced osteoclast-specific mRNA expression of cathepsin K and calcitonin receptor (CTR). In contrast, TSA and NaB did not affect the formation of bone marrow macrophages (BMMs) induced by macrophage colony-stimulating factor as examined by nonspecific esterase staining. Fluorescence-activated cell sorting analysis showed that TSA did not affect the surface expression of macrophage markers for CD11b and F4/80 of BMMs. TSA and NaB also inhibited osteoclast formation and osteoclast-specific MRNA expression in RAW264 cells stimulated with receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). Transient transfection assay revealed that TSA and NaB dose dependently reduced the sRANKL-stimulated or tumor necrosis factor α (TNF-α)-stimulated transactivation of NF-κB-dependent reporter genes. The treatment of RAW264 cells with TSA and NaB inhibited TNF-α-induced nuclear translocation of NF-κB and sRANKL-induced activation of p38 mitogen-activated protein kinase (MAPK) signals. These data suggest that both TSA and NaB exert their inhibitory effects by modulating osteoclast-specific signals and that HDAC activity regulates the process of osteoclastogenesis.

Original languageEnglish
Pages (from-to)3451-3459
Number of pages9
JournalBlood
Volume101
Issue number9
DOIs
Publication statusPublished - May 1 2003

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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