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Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors

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Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

The increasing number of osteoporosis patients is a pressing issue worldwide. Osteoporosis frequently causes fragility fractures, limiting activities of daily life and increasing mortality. Many osteoporosis patients take numerous medicines due to other health issues; thus, it would be preferable if a single medicine could ameliorate osteoporosis and other conditions. Here, we screened 96 randomly selected drugs targeting various diseases for their ability to inhibit differentiation of osteoclasts, which play a pivotal role in development of osteoporosis, and identified methotrexate (MTX), as a potential inhibitor. MTX is currently used to treat sarcomas or leukemic malignancies or auto-inflammatory diseases such as rheumatoid arthritis (RA) through its anti-proliferative and immunosuppressive activities; however, a direct effect on osteoclast differentiation has not been shown. Here, we report that osteoclast formation and expression of osteoclastic genes such as NFATc1 and DC-STAMP, which are induced by the cytokine RANKL, are significantly inhibited by MTX. We found that RANKL-dependent calcium (Ca) influx into osteoclast progenitors was significantly inhibited by MTX. RA patients often develop osteoporosis, and osteoclasts are reportedly required for joint destruction; thus, MTX treatment could have a beneficial effect on RA patients exhibiting high osteoclast activity by preventing both osteoporosis and joint destruction.

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Acknowledgments

T. Miyamoto was supported by a Grant-in-aid for Scientific Research Japan.

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    Authors and Affiliations

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

      Hiroya Kanagawa, Yuiko Sato, Yasuo Niki, Tami Kobayashi, Eri Katsuyama, Atsuhiro Fujie, Wu Hao, Toshimi Tando, Ryuichi Watanabe, Kana Miyamoto, Hideo Morioka, Morio Matsumoto, Yoshiaki Toyama & Takeshi Miyamoto

    2. Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan

      Ritsuko Masuyama

    3. Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

      Yuiko Sato

    4. Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

      Mayu Morita

    5. Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

      Hideyuki Saya

    6. Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

      Takeshi Miyamoto

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    1. Hiroya Kanagawa
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    Corresponding author

    Correspondence to Takeshi Miyamoto.

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    Additional information

    H. Kanagawa, R. Masuyama, M. Morita and Y. Sato contributed equally to this work.

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    Kanagawa, H., Masuyama, R., Morita, M. et al. Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors . J Bone Miner Metab 34, 526–531 (2016). https://doi.org/10.1007/s00774-015-0702-2

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    • DOI: https://doi.org/10.1007/s00774-015-0702-2

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