The vitamin D analogue ED71 but not 1,25(OH)2D3 targets HIF1α protein in osteoclasts

Yuiko Sato, Yoshiteru Miyauchi, Shigeyuki Yoshida, Mayu Morita, Tami Kobayashi, Hiroya Kanagawa, Eri Katsuyama, Atsuhiro Fujie, Wu Hao, Toshimi Tando, Ryuichi Watanabe, Kana Miyamoto, Hideo Morioka, Morio Matsumoto, Yoshiaki Toyama, Takeshi Miyamoto

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10 Citations (Scopus)

Abstract

Although both an active form of the vitamin D metabolite, 1,25(OH)2D3, and the vitamin D analogue, ED71 have been used to treat osteoporosis, anti-bone resorbing activity is reportedly seen only in ED71-but not in 1,25(OH)2D3 -treated patients. In addition, how ED71 inhibits osteoclast activity in patients has not been fully characterized. Recently, HIF1α expression in osteoclasts was demonstrated to be required for development of post-menopausal osteoporosis. Here we show that ED71 but not 1,25(OH)2D3, suppress HIF1α protein expression in osteoclasts in vitro. We found that 1,25(OH)2D3 or ED71 function in osteoclasts requires the vitamin D receptor (VDR). ED71 was significantly less effective in inhibiting M-CSF and RANKL-stimulated osteoclastogenesis than was 1,25(OH)2D3 in vitro. Downregulation of c-Fos protein and induction of Ifnβ mRNA in osteoclasts, both of which reportedly block osteoclastogenesis induced by 1,25(OH)2D3 in vitro, were both significantly higher following treatment with 1,25(OH)2D3 than with ED71. Thus, suppression of HIF1α protein activity in osteoclasts in vitro, which is more efficiently achieved by ED71 rather than by 1,25(OH)2D3, could be a reliable read-out in either developing or screening reagents targeting osteoporosis.

Original languageEnglish
Article numbere111845
JournalPloS one
Volume9
Issue number11
DOIs
Publication statusPublished - 2014 Nov 6

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Sato, Y., Miyauchi, Y., Yoshida, S., Morita, M., Kobayashi, T., Kanagawa, H., Katsuyama, E., Fujie, A., Hao, W., Tando, T., Watanabe, R., Miyamoto, K., Morioka, H., Matsumoto, M., Toyama, Y., & Miyamoto, T. (2014). The vitamin D analogue ED71 but not 1,25(OH)2D3 targets HIF1α protein in osteoclasts. PloS one, 9(11), [e111845]. https://doi.org/10.1371/journal.pone.0111845