Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the ERalpha.
Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the ERalpha.
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DOI：
10.1359/jbmr.091017
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Manolagas SC
中科院分区：
文献类型：
--
作者：
Almeida M;Martin-Millan M;Ambrogini E;Bradsher R 3rd;Han L;Chen XD;Roberson PK;Weinstein RS;O'Brien CA;Jilka RL;Manolagas SC
雌激素减少骨和骨髓中的氧化应激，减弱成骨细胞的生成，并降低成熟成骨细胞凋亡的发生率。我们使用携带雌激素受体α（ERα）敲入突变的小鼠模型（ERαNERKI/−）和几种表达野生型ERα或ERαNERKI/−的成骨祖细胞模型作为工具，研究了这些效应的分子机制。我们报告雌激素减少活性氧的产生，刺激谷胱甘肽还原酶的活性，减少p66 shc的磷酸化，以及成骨细胞生成和成骨细胞数量和凋亡的能力在ERαNERKI/−小鼠中得到了充分的保留，这表明ERα的DNA结合功能对所有这些作用都是无效的。与该动物模型中成骨细胞生成的减弱一致，17β-雌二醇减弱了小鼠和人成骨细胞系中骨形态发生蛋白2（BMP-2）诱导的基因转录和成骨细胞定型和分化。此外，17β-雌二醇减弱了BMP-2诱导的ERαNERKI/−小鼠颅骨或骨髓来源的成骨细胞原代培养物的分化，效果与野生型同窝仔细胞一样。该激素对BMP-2信号传导的抑制作用是由于ERα介导的ERK激活和蛋白质连接区Smad 1的磷酸化，从而导致蛋白酶体降解。这些结果表明，雌激素对氧化应激和成骨细胞的出生和死亡的影响不需要ERα与DNA反应元件的结合，而是由细胞质激酶的激活引起的。© 2010美国骨与矿物质研究学会
Estrogens diminish oxidative stress in bone and bone marrow, attenuate the generation of osteoblasts, and decrease the prevalence of mature osteoblast apoptosis. We have searched for the molecular mechanism of these effects using as tools a mouse model bearing an estrogen receptor α (ERα) knock-in mutation that prevents binding to DNA (ERαNERKI/−) and several osteoblast progenitor cell models expressing the wild-type ERα or the ERαNERKI/−. We report that the ability of estrogens to diminish the generation of reactive oxygen species, stimulate the activity of glutathione reductase, and decrease the phosphorylation of p66shc, as well as osteoblastogenesis and osteoblast number and apoptosis, were fully preserved in ERαNERKI/− mice, indicating that the DNA-binding function of the ERα is dispensable for all these effects. Consistent with the attenuation of osteoblastogenesis in this animal model, 17β-estradiol attenuated bone morphogenetic protein 2 (BMP-2)–induced gene transcription and osteoblast commitment and differentiation in murine and human osteoblastic cell lines. Moreover, 17β-estradiol attenuated BMP-2-induced differentiation of primary cultures of calvaria- or bone marrow–derived osteoblastic cells from ERαNERKI/− mice as effectively as in cells from wild-type littermates. The inhibitory effect of the hormone on BMP-2 signaling resulted from an ERα-mediated activation of ERKs and the phosphorylation of Smad1 at the linker region of the protein, which leads to proteasomal degradation. These results illustrate that the effects of estrogens on oxidative stress and the birth and death of osteoblasts do not require the binding of ERα to DNA response elements, but instead they result from the activation of cytoplasmic kinases. © 2010 American Society for Bone and Mineral Research
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