Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
J Bone Miner Res. 2013 May;28(5):1117-26. doi: 10.1002/jbmr.1842.
Estradiol (E2) is important for male skeletal health and the effect of E2 is mediated via estrogen receptor (ER)-α. This was demonstrated by the findings that men with an inactivating mutation in aromatase or a nonfunctional ERα had osteopenia and continued longitudinal growth after sexual maturation. The aim of the present study was to evaluate the role of different domains of ERα for the effects of E2 and selective estrogen receptor modulators (SERMs) on bone mass in males. Three mouse models lacking either ERαAF-1 (ERαAF-1(0)), ERαAF-2 (ERαAF-2(0)), or the total ERα (ERα(-/-)) were orchidectomized (orx) and treated with E2 or placebo. E2 treatment increased the trabecular and cortical bone mass and bone strength, whereas it reduced the thymus weight and bone marrow cellularity in orx wild type (WT) mice. These parameters did not respond to E2 treatment in orx ERα(-/-) or ERαAF-2(0). However, the effects of E2 in orx ERαAF-1(0) [corrected] were tissue-dependent, with a clear response in cortical bone parameters and bone marrow cellularity, but no response in trabecular bone. To determine the role of ERαAF-1 for the effects of SERMs, we treated orx WT and ERαAF-1(0) mice with raloxifene (Ral), lasofoxifene (Las), bazedoxifene (Bza), or vehicle. These SERMs increased total body areal bone mineral density (BMD) and trabecular volumetric BMD to a similar extent in orx WT mice. Furthermore, only Las increased cortical thickness significantly and only Bza increased bone strength significantly. However, all SERMs showed a tendency toward increased cortical bone parameters. Importantly, all SERM effects were absent in the orx ERαAF-1(0) mice. In conclusion, ERαAF-2 is required for the estrogenic effects on all evaluated parameters, whereas the role of ERαAF-1 is tissue-specific. All evaluated effects of Ral, Las and Bza are dependent on a functional ERαAF-1. Our findings might contribute to the development of bone-specific SERMs in males.
雌二醇（E2）对男性骨骼健康很重要，其作用是通过雌激素受体（ER）-α介导的。这一发现表明，芳香酶失活突变或 ERα 无功能的男性存在骨质疏松症，并在性成熟后持续纵向生长。本研究旨在评估 ERα 的不同结构域在 E2 和选择性雌激素受体调节剂（SERM）对男性骨量的影响中的作用。三种缺乏 ERαAF-1（ERαAF-1(0)）、ERαAF-2（ERαAF-2(0)）或全长 ERα（ERα(-/-)）的小鼠模型被去势（orx）并接受 E2 或安慰剂治疗。E2 治疗增加了小梁和皮质骨量和骨强度，而减少了去势野生型（WT）小鼠的胸腺重量和骨髓细胞数。这些参数在去势 ERα(-/-)或 ERαAF-2(0)小鼠中对 E2 治疗无反应。然而，E2 在去势 ERαAF-1(0)[已纠正]中的作用是组织依赖性的，皮质骨参数和骨髓细胞数有明显反应，但小梁骨无反应。为了确定 ERαAF-1 对 SERM 作用的作用，我们用雷洛昔芬（raloxifene，Ral）、拉索昔芬（lasofoxifene，Las）、巴多昔芬（bazedoxifene，Bza）或载体治疗去势 WT 和 ERαAF-1(0)小鼠。这些 SERM 在去势 WT 小鼠中以相似的程度增加了全身面积骨矿物质密度（BMD）和小梁容积 BMD。此外，只有 Las 显著增加了皮质厚度，只有 Bza 显著增加了骨强度。然而，所有 SERM 均表现出增加皮质骨参数的趋势。重要的是，所有 SERM 作用在去势 ERαAF-1(0)小鼠中均不存在。结论：ERαAF-2 是所有评估参数的雌激素作用所必需的，而 ERαAF-1 的作用是组织特异性的。Ral、Las 和 Bza 的所有评估作用都依赖于功能正常的 ERαAF-1。我们的发现可能有助于开发男性特异性的 SERM。
