title: Impaired mesenchymal stem cell differentiation and osteoclastogenesis in mice deficient for Igf2-P2 transcripts.
abstract: During embryonic development, Igf2 gene transcription is highly regulated through the use of several promoters whose specific roles are not defined. Here, we show that loss-of-function of one of these promoters, Igf2-P2, results in growth defects that are temporally and quantitatively different from those seen in Igf2-null mutants. In particular, Igf2-P2 mutants exhibit skeletal abnormalities characterized by thin and short bones with reduced mineralization and medullar cavity and with altered bone remodeling. These abnormalities are associated with decreased numbers of embryonic mesenchymal chondroprogenitors, adult mesenchymal stem cells and osteoprogenitors. Differentiation of osteoprogenitors into osteoblasts is impaired in the Igf2-P2 mutant mice in a cell-autonomous manner, and osteopontin is a target of the IGF2 signaling pathway during this differentiation. Igf2-P2 mutant mice also display impaired formation of giant osteoclasts owing to a defective micro-environment. These results support a model wherein transcriptional activity of the Igf2-P2 promoter regulates the fate of mesenchymal progenitors during bone development and remodeling in the adult, and regulates osteogenesis in a cell-autonomous and non-autonomous manner.
authors.affiliation: INSERM UMR 967, Fontenay-aux-Roses, F-92265, France. sylvie.hardouin@cea.fr
authors.forename: Sylvie Nathalie
authors.initials: SN
authors.lastname: Hardouin
authors.forename: Ruolin
authors.initials: R
authors.lastname: Guo
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Romeo
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D003114:Colony-Forming Units Assay; D004392:Dwarfism / Q000196:embryology / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D007335:Insulin-Like Growth Factor II / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008817:Mice, Mutant Strains; D009154:Mutation; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C513121:IGF2 protein, mouse; D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II