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Female Mice Lacking Estrogen Receptor-alpha in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass

Journal article
Authors Helen H. Farman
Sara H Windahl
Lars Westberg
H. Isaksson
Emil Egecioglu
Erik Schéle
Henrik Ryberg
John-Olov Jansson
J. Tuukkanen
A. Koskela
S. K. Xie
L. Hahner
J. Zehr
D. J. Clegg
Marie K Lagerquist
Claes Ohlsson
Published in Endocrinology
Volume 157
Issue 8
Pages 3242-3252
ISSN 0013-7227
Publication year 2016
Published at Institute of Neuroscience and Physiology
Centre for Bone and Arthritis Research
Institute of Neuroscience and Physiology, Department of Pharmacology
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 3242-3252
Language en
Links dx.doi.org/10.1210/en.2016-1181
Keywords trabecular bone, energy-expenditure, mineral density, midbrain raphe, leptin, osteoporosis, health, beta, osteoclasts, expression
Subject categories Clinical Medicine, Endocrinology

Abstract

Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor(ER)alpha. Central ER alpha exerts an inhibitory role on bone mass. ER alpha is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ER alpha in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ER alpha expression specifically in POMC neurons (POMC-ER alpha(-/-)). Female POMC-ER alpha(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 mu g/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-ER alpha(-/-) 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 ER alpha in VMN is involved in the regulation of bone mass, ER alpha was silenced using an adeno-associated viral vector. Silencing of ER alpha in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ER alpha in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ER alpha activity in hypothalamic POMC neuronsin ARC and stimulatory peripheral ER alpha-mediated effects in bone determines cortical bone mass in female mice.

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