title: Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2.
abstract: Estrogen receptor-α (ERα) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERα domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERα inactivation (ERα(-/-) ), (2) specific inactivation of activation function 1 (AF-1) in ERα (ERαAF-1(0) ), or (3) specific inactivation of ERαAF-2 (ERαAF-2(0) ) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ERα(-/-) mice displayed a severely reduced osteogenic response to loading with changes in cortical area (-78% ± 15%, p < 0.01) and periosteal BFR (-81% ± 9%, p < 0.01) being significantly lower than in wild-type (WT) mice. ERαAF-1(0) mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area -40% ± 11%, p < 0.05 and periosteal BFR -41% ± 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ERαAF-2(0) mice. Mechanical loading of transgenic estrogen response element (ERE)-luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE-mediated pathways. In conclusion, ERα is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2.
authors.affiliation: Department of Medicine and Clinical Nutrition, 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.forename: Leanne
authors.initials: L
authors.lastname: Saxon
authors.forename: Anna E
authors.initials: AE
authors.lastname: Börjesson
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
authors.forename: Petra
authors.initials: P
authors.lastname: Henning
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Lerner
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Galea
authors.forename: Lee B
authors.initials: LB
authors.lastname: Meakin
authors.forename: Cecilia
authors.initials: C
authors.lastname: Engdahl
authors.forename: Klara
authors.initials: K
authors.lastname: Sjögren
authors.forename: Maria C
authors.initials: MC
authors.lastname: Antal
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Lance E
authors.initials: LE
authors.lastname: Lanyon
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Price
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D013314:Stress, Mechanical; D013977:Tibia / Q000502:physiology*; D016474:Weight-Bearing
chemical_list: D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D047628:Estrogen Receptor alpha; D017370:Interleukin-11; D008024:Ligands; D012333:RNA, Messenger; D004958:Estradiol; D008156:Luciferases; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2