title: SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice.
abstract: The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)α, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ERαAF-1 for the estradiol (E2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ERαAF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ERαAF-1 (ERαAF-1(0)) with E2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ERαAF-1(0) mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ERαAF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.
authors.affiliation: Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Anna E
authors.initials: AE
authors.lastname: Börjesson
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Helen H
authors.initials: HH
authors.lastname: Farman
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Sofia
authors.initials: S
authors.lastname: Movérare-Skrtic
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Engdahl
authors.affiliation: Strasbourg University, Faculté de Médecine, Institut d'Histologie, Strasbourg, France;
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Antal
authors.affiliation: Department of Anatomy and Cell Biology, MRC Oulu, University of Oulu, Oulu, Finland;
authors.forename: Antti
authors.initials: A
authors.lastname: Koskela
authors.affiliation: Department of Anatomy and Cell Biology, MRC Oulu, University of Oulu, Oulu, Finland;
authors.forename: Juha
authors.initials: J
authors.lastname: Tuukkanen
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Hans
authors.initials: H
authors.lastname: Carlsten
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (Centre National de la Recherche Scientifique UMR7104; National de la Sante et de la Recherche Medicale U596; ULP, Collège de France), Illkirch, Strasbourg, France.
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (Centre National de la Recherche Scientifique UMR7104; National de la Sante et de la Recherche Medicale U596; ULP, Collège de France), Illkirch, Strasbourg, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Klara
authors.initials: K
authors.lastname: Sjögren
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Sara H
authors.initials: SH
authors.lastname: Windahl
authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; claes.ohlsson@medic.gu.se.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D008159:Lumbar Vertebrae / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha
keywords: activation function-1 of estrogen receptor-α; estrogen; estrogen receptor; mouse; osteoporosis; selective estrogen receptor modulators