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Membrane estrogen receptor alpha is essential for estrogen signaling in the male skeleton

Journal article
Authors Helen H. Farman
Karin L. Gustafsson
Petra Henning
Louise Grahnemo
Vikte Lionikaite
Sofia Moverare-Skrtic
Jianyao Wu
Henrik Ryberg
A. Koskela
J. Tuukkanen
E. R. Levin
Claes Ohlsson
Marie Lagerquist
Published in Journal of Endocrinology
Volume 239
Issue 3
Pages 303-312
ISSN 0022-0795
Publication year 2018
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 303-312
Language en
Keywords estrogen receptor alpha, male skeleton, bone mineral density, membrane-initiated steroid signaling, cortical bone, er-alpha, null mice, older men, estradiol, serum, mass, localization, extranuclear, specificity, Endocrinology & Metabolism, iences, v68, p1226, ates of america, v106, p2053, ates of america, v111, pe283
Subject categories Clinical Medicine


The importance of estrogen receptor alpha (ER alpha) for the regulation of bone mass in males is well established. ERa mediates estrogenic effects both via nuclear and membraneinitiated ER alpha (mER alpha) signaling. The role of mERa signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERa signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ER alpha to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (mu CT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mER alpha is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

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