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

• Published in: Journal of endocrinology Vol. 239; no. 3; pp. 303 - 312
• Main Authors: Farman, H H, Gustafsson, K L, Henning, P, Grahnemo, L, Lionikaite, V, Movérare-Skrtic, S, Wu, J, Ryberg, H, Koskela, A, Tuukkanen, J, Levin, E R, Ohlsson, C, Lagerquist, M K
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.12.2018
• Subjects: Animals; ates of america; Bone and Bones - metabolism; Bone Density; bone mineral density; Bone Remodeling; Clinical Medicine; cortical bone; Endocrinology & Metabolism; er-alpha; estradiol; estrogen receptor alpha; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; extranuclear; iences; Klinisk medicin; localization; Male; male skeleton; mass; membrane-initiated steroid signaling; Mice; null mice; older men; p1226; p2053; pe283; serum; specificity; v106; v111; v68; bone mineral density; male skeleton; membrane-initiated steroid signaling; estrogen receptor α
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1530/JOE-18-0406

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα 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 (µCT) 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, mERα 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.