NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells.
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.
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C499373:Notch3 protein, mouse; D053245:RANK Ligand; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor