The effects of estradiol are modulated in a tissue-specific manner in mice with inducible inactivation of ERα after sexual maturation

Mouse models with lifelong inactivation of estrogen receptor alpha (ERalpha) show that ERalpha is the main mediator of estrogenic effects in bone, thymus, uterus, and fat. However, ERalpha inactivation early in life may cause developmental effects that confound the adult phenotypes. To address the specific role of adult ERalpha expression for estrogenic effects in bone and other non-skeletal tissues, we established a tamoxifen-inducible ERalpha-inactivated model by crossing CAG-Cre-ER and ERalpha(flox/flox) mice. Tamoxifen-induced ERalpha-inactivation after sexual maturation substantially reduced ERalpha mRNA levels in cortical bone, trabecular bone, thymus, uterus, gonadal fat, and hypothalamus, in CAG-Cre-ERalpha(flox/flox) (inducible ERalpha(KO)) compared to ERalpha(flox/flox) (control) mice. 17beta-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 ERalpha(KO) mice compared to 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 ERalpha(KO) compared to control mice. In conclusion, using an inducible ERalpha(KO) model, not confounded by lack of ERa during development, we demonstrate that ERalpha 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 ERalpha(KO) mice strengthens the idea of cortical and trabecular bone being regulated by estrogen via different mechanisms.