Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis
Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis
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DOI：
10.1007/s10495-005-1893-0
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发表时间：
2005-05-01
期刊：
影响因子：
7.2
通讯作者：
Väänänen, HK
中科院分区：
文献类型：
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作者：
Gu, G;Hentunen, TA;Väänänen, HK
糖皮质激素诱导的骨质疏松症可能至少部分是由于骨细胞凋亡增加。为研究骨细胞凋亡在糖皮质激素诱导的骨质疏松中的作用，我们从小鼠颅骨分离了原代骨细胞，并在体外培养中分析了地塞米松的作用。通过形态学、细胞化学、免疫细胞化学染色及X染色体内肽酶同源性磷酸盐调节基因（PHEX）和硬皮病/货车Buchem病基因（SOST）的mRNA表达鉴定细胞。我们发现地塞米松以剂量依赖的方式诱导骨细胞凋亡。糖皮质激素受体拮抗剂米非司酮（RU 486）可抑制地塞米松诱导的骨细胞凋亡，提示其凋亡是由糖皮质激素受体介导的。免疫细胞化学染色显示，糖皮质激素受体存在于原代骨细胞，并在地塞米松暴露后易位到细胞核。添加雌激素阻止糖皮质激素受体易位到细胞核。用皮摩尔浓度的雌激素对原代骨细胞进行预处理后，也可观察到原代骨细胞中相应的抗凋亡作用。纯抗雌激素ICI 182，780抑制雌激素对地塞米松诱导的细胞凋亡的作用。这些数据表明，糖皮质激素受体在糖皮质激素诱导的骨细胞凋亡中起重要作用。最重要的是，雌激素对骨细胞凋亡具有保护作用。结论：激素性骨质疏松症的发生机制可能与骨细胞凋亡有关，而雌激素可拮抗激素性骨质疏松症。
Glucocorticoid-induced osteoporosis may be at least in part due to the increased apoptosis of osteocytes. To study the role of osteocyte apoptosis in glucocorticoid-induced osteoporosis, we isolated primary osteocytes from murine calvaria for the analysis of the effects of dexamethasone in in vitro culture. The cells were identified by morphology, cytochemical staining, immunocytochemical staining and mRNA expression of phosphate-regulating gene with homology to endopeptidases on the X chromosome (PHEX) and sclerosteosis/van Buchem disease gene (SOST). We found that dexamethasone induced osteocyte apoptosis in a dose-dependent manner. A glucocorticoid receptor antagonist, mifepristone (RU486), suppressed dexamethasone-Induced osteocyte apoptosis, suggesting that it was mediated by glucocorticoid receptor. Immunocytochemical stainings showed that glucocorticoid receptors are present in primary osteocytes, and they were translocated to nuclei after the exposure to dexamethasone. Addition of estrogen prevented glucocorticoid receptor translocation into nuclei. Corresponding antiapoptotic effects in primary osteocytes were also seen after the pretreatment of primary osteocytes with a picomolar concentration of estrogen. The pure antiestrogen ICI 182,780 inhibited estrogen effect on apoptosis induced by dexamethasone. These data suggest that glucocorticoid receptors play an important role in glucocorticoid-induced osteocyte apoptosis. Most importantly, estrogen has a protective effect against osteocyte apoptosis. To conclude, the mechanism of glucocorticoid-induced osteoporosis may be due to the apoptosis of osteocytes, which can be opposed by estrogen.