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

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 (HIF1 alpha), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1 alpha was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1 alpha in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1 alpha 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 alpha inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1 alpha represents a promising therapeutic target in osteoporosis.