Looking at Mountains: Role of Sustained Hypoxia in Regulating Bone Mineral Homeostasis in Relation to Wnt Pathway and Estrogen

Deteriorated bone microarchitecture is a major health concern affecting millions worldwide, amounting to high mortality along with psychological, social, and economic burden. Hypoxia has been known to affect bone mineral metabolism in various in vitro and in vivo experiments in an inconclusive manner and only a few studies are available on natives or travelers of high altitude, pointing towards the deterioration of bone health. HIF proteins, fundamental to hypoxia signaling have also been shown to affect bone remodeling by mediating osteoblastogenesis and osteoclastogenesis but the underlying mechanism of this process is not clear. Most studies have been reported in men but only few in female, while it has been already established that estrogen plays a major role in protecting skeletal health and recent reports identify estrogen as a major player in determining bone quality in men as well. The tough terrain and lack of transport in these areas require optimal bone quality to be maintained for continuous locomotion and load-bearing capacity. The Wnt pathway is involved in load-induced bone formation and sclerostin; the inhibitor of this pathway has been reported to be regulated by both estrogen and HIF proteins. However, the hypobaric hypoxia-operated molecular mechanism regulating the bone quality and microarchitecture in both male and female is still not fully elucidated. Therefore, in this review, available literature on the bone health status under sustained hypoxic exposure focusing on the significance and crosstalk of HIF proteins, Wnt pathway, and estrogen are compiled and discussed to open new aspects of high-altitude bone health research.