Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-alpha with BCAR1 and Traf6.
Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-alpha with BCAR1 and Traf6.
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DOI：
10.1016/j.yexcr.2009.01.014
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发表时间：
2009-04-15
影响因子：
3.7
通讯作者：
Blair HC
中科院分区：
文献类型：
--
作者：
Robinson LJ;Yaroslavskiy BB;Griswold RD;Zadorozny EV;Guo L;Tourkova IL;Blair HC
使用来自外周血的 CD14 选择的单核破骨细胞前体研究雌激素对破骨细胞存活和分化的影响。 ~1 nM 的雌二醇可降低 RANKL 依赖性破骨细胞分化 40-50%。添加 RANKL 后 14 天，即使 18 小时后撤回雌二醇，破骨细胞分化仍受到抑制。在 CD14+ 细胞中，细胞凋亡很少见，并且 RANKL 或 17-β-雌二醇不会增强细胞凋亡。无论雌二醇是否存在，雌激素受体-α (ERα) 的表达都会被 RANKL 强烈下调。因此，成熟的人类破骨细胞不能通过 ERα 对雌激素做出反应。然而，ERα 存在于 CD14+ 破骨细胞祖细胞中，并且在雌激素存在下结合 ERα 的支架蛋白 BCAR1 含量丰富。免疫沉淀显示 ERα-BCAR1 复合物的雌激素依赖性快速（约 5 分钟）形成，并通过 RANKL 共同处理而增加。调节 NF-κB 活性的 RANKL 信号中间体 Traf6 与该复合物一起沉淀。 RANKL 刺激后 30 分钟内，NF-κB 核定位减少，雌二醇抑制 RANKL 响应的 IκB 磷酸化。 BCAR1 的 siRNA 敲低消除了雌二醇的抑制作用。我们得出的结论是，雌激素直接但只是部分地抑制人类破骨细胞的形成。这种效应需要 BCAR1 并涉及与 ERα 的非基因组相互作用。
The effects of estrogen on osteoclast survival and differentiation were studied using CD14-selected mononuclear osteoclast precursors from peripheral blood. Estradiol at ~1 nM reduced RANKL-dependent osteoclast differentiation by 40–50%. Osteoclast differentiation was suppressed 14 days after addition of RANKL even when estradiol was withdrawn after 18 hours. In CD14+ cells apoptosis was rare and was not augmented by RANKL or by 17-β-estradiol. Estrogen receptor-α (ERα) expression was strongly down-regulated by RANKL, whether or not estradiol was present. Mature human osteoclasts thus cannot respond to estrogen via ERα. However, ERα was present in CD14+ osteoclast progenitors, and a scaffolding protein, BCAR1, which binds ERα in the presence of estrogen, was abundant. Immunoprecipitation showed rapid (~5 minute) estrogen-dependent formation of ERα-BCAR1 complexes, which were increased by RANKL co-treatment. The RANKL-signaling intermediate Traf6, which regulates NF-κB activity, precipitated with this complex. Reduction of NF-κB nuclear localization occurred within 30 minutes of RANKL stimulation, and estradiol inhibited the phosphorylation of IκB in response to RANKL. Inhibition by estradiol was abolished by siRNA knockdown of BCAR1. We conclude that estrogen directly, but only partially, curtails human osteoclast formation. This effect requires BCAR1 and involves a non-genomic interaction with ERα.
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DOI：
10.4049/jimmunol.178.6.3379
发表时间：
2007-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kovacić N;Lukić IK;Grcević D;Katavić V;Croucher P;Marusić A
通讯作者：
Marusić A
影响因子：
--
作者：
DORSSERS, LCJ;VANAGTHOVEN, T;KOK, EM
通讯作者：
KOK, EM
影响因子：
56.9
作者：
Kousteni, S;Chen, JR;Manolagas, SC
通讯作者：
Manolagas, SC
影响因子：
10.5
作者：
Lomaga, MA;Yeh, WC;Mak, TW
通讯作者：
Mak, TW
影响因子：
4.8
作者：
Darnay, BG;Ni, J;Aggarwal, BB
通讯作者：
Aggarwal, BB