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Iron overload inhibits osteoblast function and promotes osteoclastogenesis. Hepcidin plays an important role in this process. The changes in iron content and the regulation of hepcidin under unloading-induced bone loss remain unknown. A hindlimb suspension model was adopted to simulate unloading-induced bone loss in mice. The results showed that iron deposition in both liver and bone was markedly increased in hindlimb unloaded mice, and was accompanied by the upregulation of osteoclast activity and downregulation of osteoblast activity. The iron chelator deferoxamine mesylate (DFO) reduced the iron content in bone and alleviated unloading-induced bone loss. The increased iron content in bone was mainly a result of the upregulation of transferrin receptor 1 (TfR1) and divalent metal transporter 1 with iron response element (DMT1 + IRE), rather than changes in the iron transporter ferroportin 1 (FPN1). The hepcidin level in the liver was significantly higher, while the FPN1 level in the duodenum was substantially reduced. However, there were no changes in the FPN1 level in bone tissue. During hindlimb unloading, downregulation of hepcidin by siRNA increased iron uptake in bone and liver, which aggravated unloading-induced bone loss. In summary, these data show that unloading-induced bone loss was orchestrated by iron overload and coupled with the regulation of hepcidin by the liver. [ABSTRACT FROM AUTHOR]

Unloading-induced bone loss is a critical complication characterized by the imbalance of bone formation and resorption induced by long-term confinement in bed or spaceflight. CD31hiEmcnhi (type H) vessel is a specific subtype of capillary, which was coupled with osteogenesis. However, the change of type H vessel and its contributions to the unloading-induced bone loss remains undisclosed. Herein, we found that bone formation and the number of type H vessels were synchronously reduced in the hindlimb-unloading (HU) mice. Panax quinquefolium saponin (PQS) could increase bone mass, osteoblast function and the number of type H vessels in the HU mice. In vitro , PQS treatment accelerated HMECs migration, augmented the total tube loops and increased the secretion of VEGF and Noggin. Primary osteoblasts function was obviously increased when treated with supernatant from PQS-treated HMECs. These effects of PQS were substantially counteracted when VEGF and Noggin in HMECs were knocked down by siRNA. These results demonstrated that unloading-induced bone loss is coupled with reduction of type H vessels and PQS performs preventive function via promoting type H vessel angiogenesis, which is closely associated with endothelial cell-derived VEGF and Noggin. • Unloading induced bone loss is coupled with reduced numbers of type H vessel. • Panax quinquefolium saponin (PQS) facilitates type H vessel angiogenesis. • PQS protects from unloading induced bone loss. • HMEC derived VEGF and Noggin mediate the protective role of PQS in osteoblast. [ABSTRACT FROM AUTHOR]