Apoptosis prevents osteoporosis

Apoptosis prevents osteoporosis G randmothers everywhere know well that estrogen defi cits lead to osteoporosis. Now, the molecular basis for this debilitating bone loss is fi nally identifi ed. 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 diffi cult 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 androgenheaded 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.