title: Extra-nuclear effects of estrogen on cortical bone in males require ERαAF-1.
abstract: Estradiol (E2) signaling via estrogen receptor alpha (ERα) is important for the male skeleton as demonstrated by ERα inactivation in both mice and man. ERα mediates estrogenic effects not only by translocating to the nucleus and affecting gene transcription but also by extra-nuclear actions e.g., triggering cytoplasmic signaling cascades. ERα contains various domains, and the role of activation function 1 (ERαAF-1) is known to be tissue specific. The aim of this study was to determine the importance of extra-nuclear estrogen effects for the skeleton in males and to determine the role of ERαAF-1 for mediating these effects. Five-month-old male wild-type (WT) and ERαAF-1-inactivated (ERαAF-10) mice were orchidectomized and treated with equimolar doses of 17β-estradiol (E2) or an estrogen dendrimer conjugate (EDC), which is incapable of entering the nucleus and thereby only initiates extra-nuclear ER actions or their corresponding vehicles for 3.5 weeks. As expected, E2 treatment increased cortical thickness and trabecular bone volume per total volume (BV/TV) in WT males. EDC treatment increased cortical thickness in WT males, whereas no effect was detected in trabecular bone. In ERαAF-10males, E2 treatment increased cortical thickness, but did not affect trabecular bone. Interestingly, the effect of EDC on cortical bone was abolished in ERαAF-10mice. In conclusion, extra-nuclear estrogen signaling affects cortical bone mass in males, and this effect is dependent on a functional ERαAF-1. Increased knowledge regarding estrogen signaling mechanisms in the regulation of the male skeleton may aid the development of new treatment options for male osteoporosis.
authors.affiliation: Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden helen.farman@gu.se.
authors.forename: H H
authors.initials: HH
authors.lastname: Farman
authors.affiliation: Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: K L
authors.initials: KL
authors.lastname: Gustafsson
authors.affiliation: Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: S H
authors.initials: SH
authors.lastname: Windahl
authors.affiliation: Department of ChemistryUniversity of Illinois, Urbana, Illinois, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of ChemistryUniversity of Illinois, Urbana, Illinois, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M K
authors.initials: MK
authors.lastname: Lagerquist
mesh_terms: D000818:Animals; D015415:Biomarkers; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000097:blood / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D000072417:Protein Domains; D055503:Protein Multimerization
chemical_list: D015415:Biomarkers; D047628:Estrogen Receptor alpha; D004967:Estrogens
keywords: cortical bone; estrogen; estrogen dendrimer conjugate; male skeleton