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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-08-2622.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3451-3459
HEMATOPOIESIS
Two histone deacetylase inhibitors, trichostatin A and sodium
butyrate, suppress differentiation into osteoclasts but not into
macrophages
Md. Mizanur Rahman,
Akiko Kukita,
Toshio Kukita,
Takeo Shobuike,
Takahiro Nakamura, and
Osamu Kohashi
From the Department of Microbiology, Saga Medical
School, Saga, Japan; and Section of Oral Cellular and
Molecular Biology, Division of Oral Biological Science, Kyushu
University, Kyushu, Japan.
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- B
(NF-B) ligand (RANKL). Transient transfection assay revealed that
TSA and NaB dose dependently reduced the sRANKL-stimulated or tumor
necrosis factor  (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 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.
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