| First Author | Movérare-Skrtic S | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 3 | Pages | 1180-5 |
| PubMed ID | 24395795 | Mgi Jnum | J:206469 |
| Mgi Id | MGI:5550321 | Doi | 10.1073/pnas.1322910111 |
| Citation | Moverare-Skrtic S, et al. (2014) The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor alpha AF-2 is modified. Proc Natl Acad Sci U S A 111(3):1180-5 |
| abstractText | 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 ERalpha AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ERalpha AF-2 (ERalphaAF-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 ERalphaAF-2(0) mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ERalphaAF-2(0) mice. It acted as an ERalpha 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 ERalpha AF-1 in a tissue-dependent manner in mice lacking ERalphaAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ERalpha lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist. |
