The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor ? AF-2 is modified.

ABSTRACT: The bone-sparing effect of estrogen is primarily mediated via estrogen receptor (ER) ?, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. It was recently demonstrated that the ER antagonist ICI 182,780 (ICI) acts as an ER agonist in uterus of mice with mutations in the ER? AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ER? AF-2 (ER?AF-2(0)) were treated with ICI, estradiol, or vehicle for 3 wk. Estradiol increased the trabecular and cortical bone mass as well as the uterine weight, whereas it reduced fat mass, thymus weight, and the growth plate height in wild-type but not in ER?AF-2(0) mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ER?AF-2(0) mice. It acted as an ER? agonist on trabecular bone mass and uterine weight, whereas no effect was seen on cortical bone mass, fat mass, or thymus weight. Surprisingly, a pronounced inverse agonistic activity was seen on the growth plate height, resulting in enhanced longitudinal bone growth. In conclusion, ICI uses ER? AF-1 in a tissue-dependent manner in mice lacking ER?AF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ER? lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.

SUBMITTER: Moverare-Skrtic S 

PROVIDER: S-EPMC3903248 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature