Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos
Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos
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DOI：
10.1074/jbc.m313973200
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发表时间：
2004-06-18
影响因子：
4.8
通讯作者：
Wagner, EF
中科院分区：
文献类型：
--
作者：
Matsuo, K;Galson, DL;Wagner, EF
破骨细胞是吸收骨的特化巨噬细胞。缺乏AP-1组分c-Fos的小鼠由于缺乏破骨细胞分化而患有骨硬化症，并显示出巨噬细胞数量增加。c-Fos在破骨细胞分化中的关键功能的性质尚不清楚。微阵列分析显示，Nfatc 1，破骨细胞生成的另一个关键调节因子，在Fos（-/-）破骨细胞前体中下调。染色质免疫沉淀实验表明，c-Fos与破骨细胞中的Nfatc 1和Acp 5启动子结合。体外启动子分析确定了破骨细胞特异性Acp 5和Calcr启动子中的活化T细胞核因子（NFAT）/AP-1位点。此外，在Fos（-/-）前体基因转移的活性形式的NFAT恢复转录的破骨细胞特异性基因的存在下，受体活化因子的NF-κ B配体（RANKL），挽救骨吸收。然而，在不存在RANKL的情况下，与野生型前体不同，Fos（-/-）前体对NFAT诱导的破骨细胞生成不敏感。这些数据表明，Nfatc 1表达的缺乏是Fos（-/-）破骨细胞前体细胞分化阻滞的原因，Nfatc 1的转录诱导是c-Fos在破骨细胞分化中的主要功能。
Osteoclasts are specialized macrophages that resorb bone. Mice lacking the AP-1 component c-Fos are osteopetrotic because of a lack of osteoclast differentiation and show an increased number of macrophages. The nature of the critical function of c-Fos in osteoclast differentiation is not known. Microarray analysis revealed that Nfatc1, another key regulator of osteoclastogenesis, was down-regulated in Fos(-/-) osteoclast precursors. Chromatin immunoprecipitation assay showed that c-Fos bound to the Nfatc1 and Acp5 promoters in osteoclasts. In vitro promoter analyses identified nuclear factor of activated T-cells (NFAT)/AP-1 sites in the osteoclast-specific Acp5 and Calcr promoters. Moreover, in Fos(-/-) precursors gene transfer of an active form of NFAT restored transcription of osteoclast-specific genes in the presence of receptor activator of the NF-kappaB ligand (RANKL), rescuing bone resorption. In the absence of RANKL, however, Fos(-/-) precursors were insensitive to NFAT-induced osteoclastogenesis unlike wild-type precursors. These data indicate that lack of Nfatc1 expression is the cause of the differentiation block in Fos(-/-) osteoclast precursors and that transcriptional induction of Nfatc1 is a major function of c-Fos in osteoclast differentiation.