Mechanism underlying post-menopausal osteoporosis: HIF1α is required for osteoclast activation by estrogen deficiency

The aging of the population worldwide has sharply increased the number of post-menopausal osteoporosis patients. Bone fragility caused by osteoporosis often results in fractures; therefore, controlling osteoporosis is crucial to prevent such injuries. To date, various drugs to treat osteoporosis have been developed and launched; however, the molecular mechanisms underlying post-menopausal osteoporosis have not been fully elucidated, and additional factors that could be targeted to treat patients remain to be characterized. Recently, hypoxia inducible factor l alpha (HIFlα) was identified as essential for osteoclast activation, an activity that promotes bone loss following menopausal estrogen deficiency. Although osteoclasts, which are located in hypoxic regions of the bone surface, express HIFlα mRNA, in pre-menopausal conditions the presence of estrogen decreases HIFlα protein levels in these cells. In menopausal conditions, however, estrogen deficiency allows HIFlα protein to accumulate in osteoclasts, leading to osteoclast activation and bone loss. Osteoclast-specific conditional HIFlα inactivation protects mice from estrogen deficiency-induced osteoclast activation and bone loss, as does systemic administration of a HIFlα inhibitor. Therefore, HIFlα represents a potential therapeutic target to prevent osteoclast activation and bone loss in post-menopausal patients.