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HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

2013; National Academy of Sciences; Volume: 110; Issue: 41 Linguagem: Inglês

10.1073/pnas.1308755110

1091-6490

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

Cytokine Signaling Pathways and Interactions

Significance Estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder in women. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. We report a unique mechanism underlying postmenopausal osteoporosis, and a therapeutic target, hypoxia-inducible factor 1 alpha (HIF1α), to treat this condition. HIF1α is unstable in the presence of oxygen, but is stabilized under hypoxic conditions. However, we found that HIF1α is destabilized by estrogen even under hypoxic conditions. Following estrogen deficiency due to menopause, HIF1α is stabilized in osteoclasts, leading to osteoclast activation. Oral administration of a HIF1α inhibitor protected postmenopausal osteoporosis model mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.