Estrogen prevents bone loss via estrogen receptor α and induction of Fas ligand in osteoclasts

Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ER alpha) in mediating estrogendependent bone maintenance in female mice. We selectively ablated ER alpha in differentiated osteoclasts (ER alpha(Delta Oc/Delta Oc)) and found that ER alpha(Delta Oc/Delta Oc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ER alpha(Delta Oc/Delta Oc) mice. The expression of ER alpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.