25-hydroxycholesterol promotes RANKL-induced osteoclastogenesis through coordinating NFATc1 and Sp1 complex in the transcription of miR-139-5p.
25-hydroxycholesterol promotes RANKL-induced osteoclastogenesis through coordinating NFATc1 and Sp1 complex in the transcription of miR-139-5p.
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25-羟基胆固醇通过协调 miR-139-5p 转录中的 NFATc1 和 Sp1 复合物促进 RANKL 诱导的破骨细胞生成。
DOI：
10.1016/j.bbrc.2017.02.118
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Lin Yanliang
中科院分区：
文献类型：
--
作者：
Zhang Lishan;Lv Yinping;Xian Guozhe;Lin Yanliang
25-羟基胆固醇（25-HC）参与许多过程，包括脂质代谢和免疫反应。然而，25-HC在rankl诱导的破骨细胞发生中的作用在很大程度上仍然未知。我们的研究结果表明，25-HC抑制了NF-κB配体受体激活剂（RANKL）和单核细胞巨噬细胞集落刺激因子（M-CSF）培养的小鼠骨髓巨噬细胞（BMMs）中miR-139-5p的表达。进一步研究表明，25-HC可促进活化T细胞胞浆核因子1 （NFATc1）和Sp1的表达，特别是在RANKL和M-CSF存在的情况下。同时，25-HC诱导NFATc1的核易位，导致NFATc1与Sp1相互作用，共免疫沉淀证实了这一点。染色质免疫沉淀实验表明Sp1可以结合miR-139-5p启动子，而NFATc1没有结合能力。虽然形成的NFATc1/Sp1复合物增加了其与miR-139-5p启动子的结合，但该复合物抑制了Sp1的转录活性。抑制NFATc1会增加miR-139-5p的表达，这可能是由于释放了可以结合miR-139-5p启动子的游离Sp1。miR-139-5p的强制表达破坏了25-HC和RANKL共同作用诱导的破骨细胞生成。这些结果表明，25-HC诱导NFATc1和Sp1之间的相互作用，降低游离Sp1的水平，抑制miR-139-5p的表达，促进破骨细胞的发生。
25-hydroxycholesterol (25-HC) is implicated in many processes, including lipid metabolism and the immune response. However, the role of 25-HC in RANKL-induced osteoclastogenesis remains largely unknown. Our results showed that 25-HC inhibited miR-139-5p expression in mouse bone marrow macrophages (BMMs) cultured in receptor activator of NF-κB ligand (RANKL) and monocyte macrophage colony-stimulating factor (M-CSF). Further investigation suggested that 25-HC promoted the expression of nuclear factor of activated T cell cytoplasmic 1 (NFATc1) and Sp1, especially in the presence of RANKL and M-CSF. Meanwhile, 25-HC induced nuclear translocation of NFATc1, resulting in the interaction between NFATc1 and Sp1 that was confirmed by co-immunoprecipitation. Chromatin immunoprecipitation assay indicated that Sp1 could bind to miR-139-5p promoter, but NFATc1 had no binding capacity. Although forming NFATc1/Sp1 complex increased its binding to miR-139-5p promoter, the complex inhibited the transcriptional activity of Sp1. Inhibition of NFATc1 increase the expression of miR-139-5p, which might be due to the release of free Sp1 that could bind to the promoter of miR-139-5p. Enforced expression of miR-139-5p impaired osteoclastogenesis induced by co-treatment with 25-HC and RANKL. These results suggested that 25-HC induced the interaction between NFATc1 and Sp1, reducing the level of free Sp1 to inhibit miR-139-5p expression and promote osteoclastogenesis.
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