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NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2008 Mar 07; Vol. 283 (10), pp. 6509-18. Date of Electronic Publication: 2007 Dec 22. - Publication Year :
- 2008
-
Abstract
- NOTCH signaling is a key regulator of cell fate decisions in prenatal skeletal development and is active during adult tissue renewal. In addition, its association with neoplasia suggests that it is a candidate therapeutic target. We find that attenuated NOTCH signaling enhances osteoclastogenesis and bone resorption in vitro and in vivo by a combination of molecular mechanisms. First, deletion of Notch1-3 in bone marrow macrophages directly promotes their commitment to the osteoclast phenotype. These osteoclast precursors proliferate more rapidly than the wild type in response to macrophage colony-stimulating factor and are sensitized to RANKL and macrophage colony-stimulating factor, undergoing enhanced differentiation in response to low doses of either cytokine. Conforming with a role for NOTCH in this process, presentation of the NOTCH ligand JAGGED1 blunts the capacity of wild-type bone marrow macrophages to become osteoclasts. Combined, these data establish that NOTCH suppresses osteoclastogenesis via ligand-mediated receptor activation. Although NOTCH1 and NOTCH3 collaborate in regulating osteoclast formation, NOTCH1 is the dominant paralog. In addition, NOTCH1 deficiency promotes osteoclastogenesis indirectly by enhancing the ability of osteoblast lineage cells to stimulate osteoclastogenesis. This is achieved by decreasing the osteoprotegerin/RANKL expression ratio. Thus, NOTCH1 acts as a net inhibitor of bone resorption, exerting its effect both directly in osteoclast precursors and indirectly via osteoblast lineage cells. These observations raise caution that therapeutic inhibition of NOTCH signaling may adversely accelerate bone loss in humans.
- Subjects :
- Animals
Bone Marrow Cells pathology
Bone Resorption genetics
Bone Resorption pathology
Cells, Cultured
Female
Macrophage Colony-Stimulating Factor pharmacology
Male
Mice
Osteoblasts pathology
Osteoclasts pathology
RANK Ligand pharmacology
Receptor, Notch1 genetics
Receptor, Notch2 genetics
Receptor, Notch2 metabolism
Receptor, Notch3
Receptors, Notch genetics
Receptors, Notch metabolism
Signal Transduction drug effects
Signal Transduction genetics
Bone Marrow Cells metabolism
Bone Resorption metabolism
Cell Differentiation drug effects
Cell Differentiation genetics
Osteoblasts metabolism
Osteoclasts metabolism
Receptor, Notch1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 283
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18156632
- Full Text :
- https://doi.org/10.1074/jbc.M707000200