title: Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass.
abstract: Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα(-/-)). Female POMC-ERα(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα(-/-) mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: H H
authors.initials: HH
authors.lastname: Farman
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: S H
authors.initials: SH
authors.lastname: Windahl
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: L
authors.initials: L
authors.lastname: Westberg
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: H
authors.initials: H
authors.lastname: Isaksson
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: E
authors.initials: E
authors.lastname: Egecioglu
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: E
authors.initials: E
authors.lastname: Schele
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: H
authors.initials: H
authors.lastname: Ryberg
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: J O
authors.initials: JO
authors.lastname: Jansson
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: J
authors.initials: J
authors.lastname: Tuukkanen
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: A
authors.initials: A
authors.lastname: Koskela
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: S K
authors.initials: SK
authors.lastname: Xie
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: L
authors.initials: L
authors.lastname: Hahner
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: J
authors.initials: J
authors.lastname: Zehr
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: D J
authors.initials: DJ
authors.lastname: Clegg
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: M K
authors.initials: MK
authors.lastname: Lagerquist
authors.affiliation: Centre for Bone and Arthritis Research (H.H.F., S.H.W., H.R., M.K.L., C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden; Department of Pharmacology (L.W., E.E.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Biomedical Engineering (H.I.), Lund University, SE221 85 Lund, Sweden; Department of Orthopaedics (H.I.), Clinical Sciences, Lund University, SE221 85 Lund, Sweden; Institute of Neuroscience and Physiology/Endocrinology (E.S., J.O.J.), Sahlgrenska Academy, University of Gothenburg, SE405 30 Gothenburg, Sweden; Department of Clinical Chemistry (H.R.), Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden; Department of Anatomy and Cell Biology (J.T., A.K.), Institute of Cancer Research and Translational Medicine, Medical Research Center, University of Oulu, FI900 14 Oulu, Finland; and Touchstone Diabetes Center (S.K.X., L.H., J.Z., D.J.C.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: C
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects*; D000071538:Cortical Bone / Q000187:drug effects* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D011333:Pro-Opiomelanocortin