title: 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) α, 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 ERα AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ERα AF-2 (ERαAF-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 ERαAF-2(0) mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ERαAF-2(0) mice. It acted as an ERα 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 ERα AF-1 in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Movérare-Skrtic
authors.forename: Anna E
authors.initials: AE
authors.lastname: Börjesson
authors.forename: Helen H
authors.initials: HH
authors.lastname: Farman
authors.forename: Klara
authors.initials: K
authors.lastname: Sjögren
authors.forename: Sara H
authors.initials: SH
authors.lastname: Windahl
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
authors.forename: Annica
authors.initials: A
authors.lastname: Andersson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stubelius
authors.forename: Hans
authors.initials: H
authors.lastname: Carlsten
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D004965:Estrogen Antagonists / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D005260:Female; D000077267:Fulvestrant; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008024:Ligands; D051379:Mice; D009154:Mutation; D009929:Organ Size; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000737:chemistry; D020849:Raloxifene Hydrochloride / Q000737:chemistry; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D013764:Tetrahydronaphthalenes / Q000737:chemistry; D013950:Thymus Gland / Q000187:drug effects; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D014599:Uterus / Q000187:drug effects; D055114:X-Ray Microtomography
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D008024:Ligands; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013764:Tetrahydronaphthalenes; D000077267:Fulvestrant; C111332:Lasofoxifene; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D007334:Insulin-Like Growth Factor I