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A hypoxia-inducible factor stabilized by estrogen: its role in osteoporosis



DOI:10.1038/bonekey.2013.223

In this study, the authors used immunofluorescence analysis to demonstrate that hypoxia-inducible factor 1 alpha (HIF1α) was stabilized in the osteoclasts of ovariectomized (Ovx) mice with consequently low levels of estrogen. HIF1α expression was similar in Ovx mice and controls, but the protein itself appeared to be stabilized in the absence of estrogen.

Knockout mice generated with a specific knockdown of HIF1α expression in osteoclasts did not differ appreciably from sham control mice in terms of bone mineral density, osteoclast formation or other bone parameters. However, the HIF1α knockout mice did not exhibit bone loss after ovariectomization, suggesting that the presence of estrogen normally suppresses HIF1α, preventing activation of osteoclasts. Cell culture studies with osteoclasts with an estrogen receptor α (ERα) knockdown, and generation of a mouse strain with a double conditional knockout of HIF1α and ERα revealed that the protective effect of estrogen was mediated through this estrogen receptor in vitro and in vivo.

Ovx mice treated with 2-methoxyestradiol, which inhibits HIF1α, had similar levels of osteoclast activation to sham controls, and their bone mineral density was greater than that of untreated Ovx mice.

Editor’s comment: Deletion of HIF1α in osteoclasts, or down-regulation of HIF1α protein by a HIF1α synthesis inhibitor, antagonizes bone loss induced by estrogen deficiency. HIF1α should therefore be considered as a new therapeutic target for postmenopausal osteoporosis.


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