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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-08-2622.
Submitted August 28, 2002
Accepted December 18, 2002
Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages
Rahman M Mizanur, Akiko Kukita*, Toshio Kukita, Takeo Shobuike, Takahiro Nakamura, and Osamu Kohashi
Department of Microbiology, Saga Medical School, Saga, Japan
Division of Oral Biological Science, Kyushu University, Fukuoka, Japan
* Corresponding author; email: kukita{at}post.saga-med.ac.jp.
Histone deacetylase (HDAC) inhibitors are emerging as a new class of anti-cancer 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 two 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 RT-PCR 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 (BMM) induced by M-CSF as examined by NSE staining. FACS analysis showed that TSA did not affect the surface expression of macrophage markers for CD11b and F4/80 of BMM. TSA and NaB also inhibited osteoclast formation and osteoclast-specific mRNA expression in RAW264 cells stimulated with receptor activator of NF- B ligand (RANKL). Transient transfection assay revealed that TSA and NaB dose-dependently reduced the sRANKL- or TNF -stimulated transactivation of NF-B-dependent reporter genes. The treatment of RAW264 cells with TSA and NaB inhibited TNF-induced nuclear translocation of NF-B and sRANKL-induced activation of p38 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.
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