Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
J Endocrinol. 2018 Dec 1;239(3):303-312. 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.
雌激素受体 α（ERα）对男性骨量的调节作用是明确的。ERα 通过核和膜起始 ERα（mERα）信号转导来介导雌激素的作用。mERα 信号转导在雄性小鼠中对雌激素对骨骼的作用尚不清楚。为了研究 mERα 信号转导的作用，我们使用了一种点突变（C451A）的小鼠（仅核 ER；NOER），该突变导致 ERα向质膜的转运受到抑制。用双能 X 射线吸收法（DEXA）测量，与 WT 同窝仔相比，去势雄性 NOER 小鼠在 3、6 和 9 个月时的全身骨面积骨密度（aBMD）明显降低。3 月龄雄性小鼠胫骨的高分辨率微计算机断层扫描（µCT）分析显示，NOER 小鼠的皮质和小梁厚度与 WT 同窝仔相比有所降低。如预期的那样，雌激素（E2）治疗去势 WT 小鼠可增加全身 aBMD、胫骨小梁 BV/TV 和皮质厚度，与安慰剂治疗相比。E2 治疗也增加了 ORX NOER 小鼠的这些骨骼参数。然而，与 ORX WT 小鼠相比，ORX NOER 小鼠的雌激素反应明显降低。总之，mERα 对于雄性小鼠的骨小梁和皮质骨中正常的雌激素信号转导是必需的。增加对调节男性骨骼的雌激素信号转导机制的了解，可能有助于开发新的男性骨质疏松症治疗选择。
