HIF1alpha is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis.
Fiche publication
Date publication
octobre 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre, Dr KOBAYASHI Toshihide
Tous les auteurs :
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 RS, Kato S, Toyama Y, Miyamoto T
Lien Pubmed
Résumé
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 (HIF1alpha), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1alpha was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1alpha in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1alpha 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 HIF1alpha inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1alpha represents a promising therapeutic target in osteoporosis.
Référence
Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16568-73