title: Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma.
abstract: Mesenchymal precursor cells have the potential to differentiate into several cell types, including adipocytes and osteoblasts. Activation of Wnt/beta-catenin signaling shifts mesenchymal cell fate toward osteoblastogenesis at the expense of adipogenesis; however, molecular mechanisms by which Wnt signaling alters mesenchymal cell fate have not been fully investigated. Our prior work indicates that multipotent precursors express adipogenic and osteoblastogenic transcription factors at physiological levels and that ectopic expression of Wnt10b in bipotential ST2 cells suppresses expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) and increases expression of Runx2, Dlx5, and osterix. Here, we demonstrate that transient activation of Wnt/beta-catenin signaling rapidly suppresses C/EBPalpha and PPARgamma, followed by activation of osteoblastogenic transcription factors. Enforced expression of C/EBPalpha or PPARgamma partially rescues lipid accumulation and decreases mineralization in ST2 cells expressing Wnt10b, suggesting that suppression of C/EBPalpha and PPARgamma is required for Wnt/beta-catenin to alter cell fate. Furthermore, knocking down expression of C/EBPalpha, PPARgamma, or both greatly reduces adipogenic potential and causes spontaneous osteoblastogenesis in ST2 cells and mouse embryonic fibroblasts, suggesting that Wnt signaling alters the fate of mesenchymal precursor cells primarily by suppressing C/EBPalpha and PPARgamma.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109-0622, USA.
authors.forename: Sona
authors.initials: S
authors.lastname: Kang
authors.forename: Christina N
authors.initials: CN
authors.lastname: Bennett
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gerin
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Rapp
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Hankenson
authors.forename: Ormond A
authors.initials: OA
authors.lastname: Macdougald
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010012:Osteogenesis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D050659:Core Binding Factor Alpha 1 Subunit; C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; D047495:PPAR gamma; C493716:Runx2 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D051176:beta Catenin