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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
JournalJournal of Bone and Mineral Metabolism
DOIs
Publication statusAccepted/In press - 2015 Jul 23

Fingerprint

Osteoclasts
Osteogenesis
Methotrexate
Osteoporosis
Calcium
Rheumatoid Arthritis
Joints
Drug Delivery Systems
Immunosuppressive Agents
Sarcoma
Medicine
Cytokines
Gene Expression
Mortality
Health
Neoplasms

Keywords

  • Calcium influx
  • Differentiation
  • Methotrexate
  • Osteoclast

ASJC Scopus subject areas

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

Cite this

Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors. / Kanagawa, Hiroya; Masuyama, Ritsuko; Morita, Mayu; Sato, Yuiko; Niki, Yasuo; Kobayashi, Tami; Katsuyama, Eri; Fujie, Atsuhiro; Hao, Wu; Tando, Toshimi; Watanabe, Ryuichi; Miyamoto, Kana; Morioka, Hideo; Matsumoto, Morio; Toyama, Yoshiaki; Saya, Hideyuki; Miyamoto, Takeshi.

In: Journal of Bone and Mineral Metabolism, 23.07.2015.

Research output: Contribution to journalArticle

Kanagawa, H, Masuyama, R, Morita, M, Sato, Y, Niki, Y, Kobayashi, T, Katsuyama, E, Fujie, A, Hao, W, Tando, T, Watanabe, R, Miyamoto, K, Morioka, H, Matsumoto, M, Toyama, Y, Saya, H & Miyamoto, T 2015, 'Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors', Journal of Bone and Mineral Metabolism. https://doi.org/10.1007/s00774-015-0702-2
Kanagawa, Hiroya ; Masuyama, Ritsuko ; Morita, Mayu ; Sato, Yuiko ; Niki, Yasuo ; Kobayashi, Tami ; Katsuyama, Eri ; Fujie, Atsuhiro ; Hao, Wu ; Tando, Toshimi ; Watanabe, Ryuichi ; Miyamoto, Kana ; Morioka, Hideo ; Matsumoto, Morio ; Toyama, Yoshiaki ; Saya, Hideyuki ; Miyamoto, Takeshi. / Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors. In: Journal of Bone and Mineral Metabolism. 2015.
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