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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-06-1740.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2227-2234
HEMATOPOIESIS
Regulation of osteoclast development by Notch signaling directed
to osteoclast precursors and through stromal cells
Takayuki Yamada,
Hidetoshi Yamazaki,
Toshiyuki Yamane,
Miya Yoshino,
Hiromi Okuyama,
Motokazu Tsuneto,
Tomomi Kurino,
Shin-Ichi Hayashi, and
Seiji Sakano
From the Division of Immunology, Department of
Molecular and Cellular Biology, School of Life Science, Faculty of
Medicine, Tottori University, Yonago, Tottori, Japan; and the Second
Research Department, Central Technology Laboratory, Asahi Kasei,
Shizuoka, Japan.
Osteoclasts are derived from hematopoietic precursor cells
belonging to the monocyte/macrophage lineage. Osteoclast
development has been reported to be regulated by several molecules such
as macrophage colony-stimulating factor (M-CSF), receptor activator of
nuclear factor (NF)- B ligand (RANKL), and a decoy receptor of RANKL, osteoprotegerin (OPG). Recently, it was demonstrated that the
Notch signaling pathway regulates myeloid differentiation and
antagonizes cell fate determination, however, the effect of Notch
signaling on the osteoclast lineage has not been reported. In this
study, we examined the effect of signaling via Notch receptors on the
differentiation into osteoclasts by using cells from the bone marrow,
spleen, and peritoneal cavity, and a cloned macrophagelike cell line.
Osteoclastogenesis was inhibited by an immobilized Notch ligand,
Delta-1. The dish-adherent bone marrow cells precultured with
M-CSF expressed both Mac-1 and M-CSF receptors, c-Fms;
osteoclastogenesis of these cells was efficiently inhibited. The
immobilized Delta-1 also down-regulated the surface c-Fms expression,
while the c-Fms gene expression was not changed. Genes for
Notch receptors and Notch ligands are expressed in not only
hematopoietic cells but also stromal cells that support osteoclast
development. Constitutively active Notch1-transfected
stromal cells showed increased expression of RANKL and OPG genes, and
strong inhibition of M-CSF gene expression, resulting in reduction of
their ability to support osteoclast development. Taken together, these
findings indicate that Notch signaling affects both osteoclast
precursors and stromal cells and thereby negatively regulates osteoclastogenesis.
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