Editors' ChoicePhysiology

Preventing Bone Loss

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Science Signaling  15 Oct 2013:
Vol. 6, Issue 297, pp. ec247
DOI: 10.1126/scisignal.2004804

Bone mass is regulated by the opposing actions of bone-forming osteoblasts and bone-resorbing osteoclasts. Bone loss (osteoporosis) can be induced by estrogen deficiency and often occurs in postmenopausal women. Using mouse models of postmenopausal osteoporosis, Miyauchi et al. found that hypoxia-inducible factor 1α (HIF1α) was critical to bone resorption. Compared with controls, ovariectomized mice had decreased estrogen production and increased abundance of HIF1α at the protein, but not mRNA, level in osteoclasts that were localized to hypoxic regions of hind limb bones. Treating primary osteoclast cultures from wild-type mice with β-estradiol (E2) decreased the abundance of HIF1α without affecting its transcript in either hypoxic or normoxic conditions, but E2 had no effect in cultures derived from mice with osteoclast-specific conditional knockout of estrogen receptor α (ERα), suggesting that estrogen destabilizes HIF1α in an ERα-dependent manner. Osteoclast-specific conditional knockout of HIF1α prevented osteoclastogenesis and decreased serum CTx (a marker of bone resorption) after ovariectomy. Whereas osteoclastogenesis in bone marrow–derived cultures from control or HIF1α-knockout mice was similar under normoxic culture conditions, HIF1α-knockout cultures exhibited reduced expression of Ctsk, which encodes osteoclast marker cathepsin K, under hypoxic conditions compared with controls. Whereas E2 treatment reduced Ctsk expression in control cells, E2 had no effect in HIF1α-knockout cells, indicating that HIF1α is critical to hypoxia-induced bone loss and that estrogen prevents this by destabilizing HIF1α. Although HIF1α is degraded through the ubiquitin-proteasome machinery, inhibitors of serine or cysteine proteases, calpains, or the proteasome failed to block E2-induced HIF1α destabilization, suggesting that it occurs through a unique mechanism. Mice treated with an oral posttranscriptional inhibitor of HIF1α, 2-methoxyestradiol (an ER agonist), showed decreased serum CTx and increased bone mass density after ovariectomy compared with untreated mice. The findings suggest that HIF1α may be a promising target for osteoporosis therapy.

Y. Miyauchi, Y. Sato, T. Kobayashi, S. Yoshida, T. Mori, H. Kanagawa, E. Katsuyama, A. Fujie, W. Hao, K. Miyamoto, T. Tando, H. Morioka, M. Matsumoto, P. Chambon, R. S. Johnson, S. Kato, Y. Toyama, T. Miyamoto, HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. Proc. Natl. Acad. Sci. U.S.A. 110, 16568–16573 (2013).[Abstract][Full Text]