Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes

Kunihiro Hisada, Kenji Hata, Fumitaka Ichida, Takuma Matsubara, Hideo Orimo, Tamaki Nakano, Hirohumi Yatani, Riko Nishimura, Toshiyuki Yoneda

    Research output: Contribution to journalArticlepeer-review

    36 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)53-63
    Number of pages11
    JournalJournal of Bone and Mineral Metabolism
    Volume31
    Issue number1
    DOIs
    Publication statusPublished - 2013 Jan

    Keywords

    • Adipocyte
    • Bone morphogenetic protein
    • Osteoblast
    • Retinoic acid

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Orthopedics and Sports Medicine
    • Endocrinology

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