The Effects Of Estradiol Are Modulated In A Tissue-Specific Manner In Mice With Inducible Inactivation Of Era After Sexual Maturation

Mouse models with lifelong inactivation of estrogen receptor-alpha (ER alpha) show that ER alpha is the main mediator of estrogenic effects in bone. thymus, uterus. and fat. However, ER alpha inactivation early in life may cause developmental effects that confound the adult phenotypes. To address the specific role of adult ER alpha expression for estrogenic effects in bone and other nonskeletal tissues, we established a tamoxifen-inducible ER alpha-inactivated model by crossing CAGG-Cre-ER and ER alpha(flox/flox) mice. Tamoxifen-induced ER alpha inactivation after sexual maturation substantially reduced ER alpha mRNA levels in cortical bone, trabecular bone, thymus. uterus, gonadal fat. and hypothalamus, in CAGG-Cre-ER alpha(flox/flox) (inducible ER alpha(KO)) compared with ER alpha(flox/flox) (control) mice. 17 beta-estradiol (E2) treatment increased trabecular bone volume fraction (BV/TV), cortical bone area, and uterine weight, while it reduced thymus weight and fat mass in ovariectomized control mice. The estrogenic responses were substantially reduced in inducible ER alpha(KO) mice compared with control mice on BV/TV (-67%), uterine weight (-94%), thymus weight (-70%). and gonadal fat mass (-94%). In contrast, the estrogenic response on cortical bone area was unaffected in inducible ER alpha(KO) compared with control mice. In conclusion, using an inducible ER alpha(KO) model, not confounded by lack of ER alpha during development, we demonstrate that ER alpha expression in sexually mature female mice is required for normal E2 responses in most, but not all, tissues. The finding that cortical, but not trabecular bone, responds normally to E2 treatment in inducible ER alpha(KO) mice strengthens the idea of cortical and trabecular bone being regulated by estrogen via different mechanisms.