HIF1? is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

Yoshiteru Miyauchi, Yuiko Sato, Tami Kobayashi, Shigeyuki Yoshida, Tomoaki Mori, Hiroya Kanagawa, Eri Katsuyama, Atsuhiro Fujie, Wu Hao, Kana Miyamoto, Toshimi Tando, Hideo Morioka, Morio Matsumoto, Pierre Chambon, Randall S. Johnson, Shigeaki Kato, Yoshiaki Toyama, Takeshi Miyamoto

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Abstract

In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogendependent destabilization of hypoxia-inducible factor 1 alpha (HIF1?), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1? was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1? in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1? inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1? inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1? represents a promising therapeutic target in osteoporosis.

Original languageEnglish
Pages (from-to)16568-16573
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number41
DOIs
Publication statusPublished - 2013 Oct 8

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Miyauchi, Y., Sato, Y., Kobayashi, T., Yoshida, S., Mori, T., Kanagawa, H., Katsuyama, E., Fujie, A., Hao, W., Miyamoto, K., Tando, T., Morioka, H., Matsumoto, M., Chambon, P., Johnson, R. S., Kato, S., Toyama, Y., & Miyamoto, T. (2013). HIF1? is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. Proceedings of the National Academy of Sciences of the United States of America, 110(41), 16568-16573. https://doi.org/10.1073/pnas.1308755110