title: HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis.
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, estrogen-dependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α 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 HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.
authors.affiliation: Departments of Orthopedic Surgery, Integrated Bone Metabolism and Immunology, and Musculoskeletal Reconstruction and Regeneration Surgery, Keio Kanrinmaru Project, and Department of Dentistry and Oral Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Miyauchi
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kanagawa
authors.forename: Eri
authors.initials: E
authors.lastname: Katsuyama
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Fujie
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Toshimi
authors.initials: T
authors.lastname: Tando
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D016133:Polymerase Chain Reaction
chemical_list: D004967:Estrogens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol
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