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

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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.

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Acknowledgments

We thank Dr. Minoru Morikawa, Dr. Yoshiaki Ito, Dr. Shizuo Akira, Dr. Bruce M. Spiegelman. and Dr. Takeshi Imamura for providing 3T3-F442A cell line cells, Runx2 cDNA, C/EBPβ and C/EBPδ cDNA, aP2 gene promoter construct, and SBE luciferase construct, respectively. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Uehara Memorial Foundation and the Astellas Foundation for Research on Metabolic Disorders.

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All authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Kunihiro Hisada, Kenji Hata, Fumitaka Ichida, Takuma Matsubara, Riko Nishimura & Toshiyuki Yoneda

  2. Department of Fixed Prosthodontics, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Kunihiro Hisada, Tamaki Nakano & Hirohumi Yatani

  3. Division of Metabolism and Nutrition, Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan

    Hideo Orimo

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  1. Kunihiro Hisada
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Correspondence to Riko Nishimura.

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Hisada, K., Hata, K., Ichida, F. et al. Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. J Bone Miner Metab 31, 53–63 (2013). https://doi.org/10.1007/s00774-012-0385-x

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  • DOI: https://doi.org/10.1007/s00774-012-0385-x

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