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1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression

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Abstract

1-Alpha, 25-dihydroxy vitamin D3 (1α,25(OH)2D3), an active form of vitamin D3, plays a critical role in calcium and bone metabolism. Although 1α,25(OH)2D3 has been used for osteoporosis therapy, the direct role of 1α,25(OH)2D3 on human osteoclastogenesis has not been well characterized. Here we show that 1α,25(OH)2D3 treatment significantly inhibited human osteoclast formation at the early stage of differentiation in a concentration-dependent manner. 1α,25(OH)2D3 inhibited the expression of nuclear factor of activated T cells c1 (NFATc1, also referred as NFAT2), an essential transcription factor for osteoclast differentiation, and upregulated the expression of interferon-β (IFN-β), a strong inhibitor of osteoclastogenesis in osteoclast progenitors. Inhibitory effects of 1α,25(OH)2D3 on osteoclastogenesis and NFATc1 expression were restored by treatment with an antibody against IFN-β, suggesting that upregulation of IFN-β by 1α,25(OH)2D3 treatment results in inhibition of NFATc1 expression, in turn interfering with osteoclast formation. Thus, our study may provide a molecular basis for the treatment of human bone diseases by 1α,25(OH)2D3 through regulation of the IFN-β and NFATc1 axis.

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Acknowledgments

We thank Y. Sato for technical support. T. Miyamoto was supported by Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Japan Society for the Promotion of Science Fujita Memorial Fund for Medical Research, and a grant-in-aid from the Global COE Program of the Ministry of Education, Culture, Sports, Science and Technology, Japan, to Keio University.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Sadaoki Sakai, Hironari Takaishi, Kenichiro Matsuzaki, Hironori Kaneko, Mitsuru Furukawa, Yoshiteru Miyauchi, Takeshi Miyamoto & Yoshiaki Toyama

  2. Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan

    Sadaoki Sakai, Ayako Shiraishi & Keiji Saito

  3. Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, Tokyo, Japan

    Takeshi Miyamoto

  4. Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan

    Toshio Suda

  5. Medical Business and Science Sales Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    Sadaoki Sakai & Akio Tanaka

  6. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan

    Tadatsugu Taniguchi

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  1. Sadaoki Sakai
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Correspondence to Takeshi Miyamoto.

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Sakai, S., Takaishi, H., Matsuzaki, K. et al. 1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression. J Bone Miner Metab 27, 643–652 (2009). https://doi.org/10.1007/s00774-009-0084-4

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  • DOI: https://doi.org/10.1007/s00774-009-0084-4

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