Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells.
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)-kappaB 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.
Yamada
Takayuki
T
Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan. yamad@grape.med.tottori-u.ac.jp
Yamazaki
Hidetoshi
H
Yamane
Toshiyuki
T
Yoshino
Miya
M
Okuyama
Hiromi
H
Tsuneto
Motokazu
M
Kurino
Tomomi
T
Hayashi
Shin-Ichi
S
Sakano
Seiji
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001854:Bone Marrow Cells / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000032:analysis; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology*; D053244:Osteoprotegerin; D016133:Polymerase Chain Reaction; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000032:analysis; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D051880:Receptors, Notch; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D006023:Glycoproteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016173:Macrophage Colony-Stimulating Factor; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D051880:Receptors, Notch; D018124:Receptors, Tumor Necrosis Factor; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; C064045:delta protein