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

Abstract

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor (ER) alpha, 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 alpha AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ER alpha AF-2 (ER alpha AF2 degrees) 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 alpha AF-2 degrees mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ER alpha AF-2 degrees mice. It acted as an ER alpha 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 ERa AF-1 in a tissue-dependent manner in mice lacking ER alpha AF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ERa lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.