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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor pathways.
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Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor pathways.

机译：雌激素的骨架作用是由经典和非经典雌激素受体途径的相反作用介导的。

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ER alpha acts either through classical (ERE-mediated) or nonclassical (non-ERE) pathways. The generation of mice carrying a mutation that eliminates classical ER alpha signaling presents a unique opportunity to study the relative roles of these pathways in bone. This study defines the skeletal phenotype and responses to ovariectomy and estrogen replacement in these mice. INTRODUCTION: Estrogen receptor alpha (ER alpha) can act either through classical estrogen response elements (EREs) or through non-ERE (nonclassical) pathways. To unravel these in bone, we crossed mice heterozygous for a knock-in mutation abolishing ERE binding (nonclassical ER alpha knock-in [NERKI]) with heterozygote ER alpha knockout mice and studied the resulting female ER alpha(+/+), ER alpha(+/NERKI), and ER alpha(-/NERKI) mice. The only ER alpha present in ER alpha(-/NERKI) mice is incapable of activating EREs but can signal through nonclassical pathways, whereas ER alpha(+/NERKI) mice may have a less drastic alteration in the balance between classical and nonclassical estrogen signaling pathways. MATERIALS AND METHODS: BMD was measured using DXA and pQCT at 3 months of age (n = 46-48/genotype). The mice were randomly assigned to sham surgery, ovariectomy, ovariectomy + estradiol (0.25 microg/day), or ovariectomy + estradiol (1.0 microg/day; n = 10-12/group) and restudied 60 days later. RESULTS AND CONCLUSIONS: At 3 months of age, both the ER alpha(+/NERKI) and ER alpha(-/NERKI) mice had deficits in cortical, but not in trabecular, bone. Remarkably, changes in cortical bone after ovariectomy and estrogen replacement in ER alpha(-/NERKI) mice were the opposite of those in ER alpha(+/+) mice. Relative to sham mice, ovariectomized ER alpha(-/NERKI) mice gained more bone (not less, as in ER alpha(+/+) mice), and estrogen suppressed this increase (whereas augmenting it in ER alpha(+/+) mice). Estrogen also had opposite effects on bone formation and resorption parameters on endocortical surfaces in ER alpha(-/NERKI) versus ER alpha(+/+) mice. Collectively, these data show that alteration of the balance between classical and nonclassical ER alpha signaling pathways leads to deficits in cortical bone and also represent the first demonstration, in any tissue, that complete loss of classical ERE signaling can lead to paradoxical responses to estrogen. Our findings strongly support the hypothesis that there exists a balance between classical and nonclassical ER alpha signaling pathways, which, when altered, can result in a markedly aberrant response to estrogen.
机译：ER alpha通过经典（ERE介导）或非经典（non-ERE）途径起作用。携带消除经典ERα信号传导突变的小鼠代，为研究这些途径在骨骼中的相对作用提供了独特的机会。这项研究定义了这些小鼠的骨骼表型以及对卵巢切除和雌激素替代的反应。简介：雌激素受体α（ER alpha）可以通过经典的雌激素反应元件（ERE）或通过非ERE（非经典）途径发挥作用。为了弄清它们在骨骼中的分布，我们将杂合子与杂合子ER alpha敲除小鼠杂交，以获得消除ERE结合的敲入突变（非经典ER alpha敲入[NERKI]），并研究了产生的雌性ER alpha（+ / +），ER alpha（+ / NERKI）和ER alpha（-/ NERKI）小鼠。 ER alpha（-/ NERKI）小鼠中存在的唯一ER alpha无法激活ERE，但可以通过非经典途径发出信号，而ER alpha（+ / NERKI）小鼠在经典和非经典雌激素信号传导之间的平衡变化可能较小途径。材料与方法：使用DXA和pQCT在3个月大时测量BMD（n = 46-48 /基因型）。将小鼠随机分为假手术，卵巢切除术，卵巢切除术+雌二醇（0.25微克/天）或卵巢切除术+雌二醇（1.0微克/天; n = 10-12 /组），并在60天后进行了研究。结果与结论：在3个月大时，ER alpha（+ / NERKI）和ER alpha（-/ NERKI）小鼠的皮质骨均缺乏，但小梁骨中没有。值得注意的是，ER alpha（-/ NERKI）小鼠卵巢切除和雌激素替代后皮质骨的变化与ER alpha（+ / +）小鼠相反。相对于假小鼠，卵巢切除的ER alpha（-/ NERKI）小鼠获得了更多的骨骼（而不是更少，如ER alpha（+ / +）小鼠一样），并且雌激素抑制了这种增加（而在ER alpha（+ / +）中增加了它）老鼠）。雌激素对ER alpha（-/ NERKI）和ER alpha（+ / +）小鼠的骨形成和皮质内表面上的吸收参数也具有相反的影响。总的来说，这些数据表明，经典和非经典ERα信号通路之间平衡的改变导致皮质骨缺损，并且也代表了在任何组织中经典ERE信号的完全丧失会导致对雌激素的悖论反应的第一个证明。我们的发现强烈支持以下假设：经典的和非经典的ER alpha信号传导途径之间存在平衡，当这种变化被改变时，可能导致对雌激素的异常反应。

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