title: Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation.
abstract: Postnatal bone marrow houses mesenchymal progenitor cells that are osteoblast precursors. These cells have established therapeutic potential, but they are difficult to maintain and expand in vitro, presumably because little is known about the mechanisms controlling their fate decisions. To investigate the potential role of Notch signaling in osteoblastogenesis, we used conditional alleles to genetically remove components of the Notch signaling system during skeletal development. We found that disruption of Notch signaling in the limb skeletogenic mesenchyme markedly increased trabecular bone mass in adolescent mice. Notably, mesenchymal progenitors were undetectable in the bone marrow of mice with high bone mass. As a result, these mice developed severe osteopenia as they aged. Moreover, Notch signaling seemed to inhibit osteoblast differentiation through Hes or Hey proteins, which diminished Runx2 transcriptional activity via physical interaction. These results support a model wherein Notch signaling in bone marrow normally acts to maintain a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway.
authors.affiliation: Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hilton
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tu
authors.forename: Ximei
authors.initials: X
authors.lastname: Wu
authors.forename: Shuting
authors.initials: S
authors.lastname: Bai
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhao
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
mesh_terms: D000375:Aging; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001846:Bone Development / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D017353:Gene Deletion; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology*; D010641:Phenotype; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases