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

研究成果: Article査読

164 被引用数 (Scopus)


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.

ジャーナルProceedings of the National Academy of Sciences of the United States of America
出版ステータスPublished - 2013 10月 8

ASJC Scopus subject areas

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