title: Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes.
abstract: Evidence indicates that the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells (MSCs) is regulated by several hormones, growth factors, and their downstream signaling cascades. Previous studies suggest that retinoic acid (RA) plays a role in osteoblastogenesis and adipogenesis. However, it is unknown whether RA regulates commitment of MSCs into osteoblasts and adipocytes. In this study, we investigated the role of RA in differentiation of MSCs using the C3H10T1/2 cell line. RA stimulated activity and expression of alkaline phosphatase (ALP) and upregulated activity of the ALP gene promoter. The effects of RA were further enhanced by bone morphogenetic protein 2 (BMP2) and resultant Smad signaling. Furthermore, overexpression of Runx2 and Msx2, critical transcription factors for bone formation and BMP2-dependent osteoblastogenesis, enhanced RA-dependent ALP activity. In view of these findings, RA likely stimulates osteoblast differentiation through the BMP2-Smad-Runx2/Msx2 pathway. In contrast, RA markedly inhibited BMP2-induced adipocyte differentiation, suppressing expression of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein (C/EBP)α and C/EBPδ, and inhibiting adipogenic function of C/EBPβ, C/EBPδ, and PPARγ. In conclusion, our data suggest that RA regulates commitment of MSCs into osteoblasts and adipocytes by controlling transcriptional regulators.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hisada
authors.forename: Kenji
authors.initials: K
authors.lastname: Hata
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ichida
authors.forename: Takuma
authors.initials: T
authors.lastname: Matsubara
authors.forename: Hideo
authors.initials: H
authors.lastname: Orimo
authors.forename: Tamaki
authors.initials: T
authors.lastname: Nakano
authors.forename: Hirohumi
authors.initials: H
authors.lastname: Yatani
authors.forename: Riko
authors.initials: R
authors.lastname: Nishimura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C530718:CEBPA protein, mouse; C497252:CEBPD protein, human; C497253:Cebpd protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D018398:Homeodomain Proteins; C084119:MSX2 protein; D047495:PPAR gamma; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; D051785:Smad Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta; D014212:Tretinoin; D000469:Alkaline Phosphatase