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Apoptosis prevents osteoporosis

The survival of osteoclasts (top, purple) in mice lacking estrogen receptors (right) leads to loss of bone mass (bottom). KATO/ELSEVIER

Grandmothers everywhere know well that estrogen deficits lead to osteoporosis. Now, the molecular basis for this debilitating bone loss is finally identified. Estrogen is needed to kill off bone-destroying osteoclasts, show Takashi Nakamura, Shigeaki Kato (University of Tokyo, Japan), and colleagues.

The root cause of osteoporosis has been difficult to pin down, in part because bones are not frail in female mice lacking estrogen receptors. These mice make extra androgen, which builds bone in male mice and might compensate for bone loss in the mutant females.

To avoid the androgen rise, Kato's group knocked out estrogen receptors only in mature osteoclasts, which accumulate in osteoporotic bones. These female mutants developed rickety bones due to losses within the central bone shafts.

The authors then isolated osteoclasts to determine why they are so abundant in diseased bone. Microarray analyses revealed that estrogen induced apoptotic proteins, including Fas ligand, that were not induced in the estrogen-blind osteoclasts.

Men who have estrogen receptor mutations develop osteoporosis. But male mice were not affected by the loss of estrogen receptors in osteoclasts. Perhaps the androgen-headed pathway is more dominant in mice than in humans.

Currently, potential drugs to treat osteoporosis are screened through mice whose ovaries have been removed. Screens for the induction of Fas ligand in cultures of estrogen-blind osteoclasts should be much simpler.

Reference:

Nakamura, T., et al. 2007. Cell. 130:811–823.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 872K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?