Autoamplification of NFATc1 expression determines its essential role in bone homeostasis
Autoamplification of NFATc1 expression determines its essential role in bone homeostasis
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DOI：
10.1084/jem.20051150
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发表时间：
2005-11-07
影响因子：
15.3
通讯作者：
Takayanagi, H
中科院分区：
文献类型：
--
作者：
Asagiri, M;Sato, K;Takayanagi, H
NFATc 1和NFATc 2在免疫系统中是功能冗余的，但有人认为NFATc 1是骨骼系统中破骨细胞分化所必需的。在这里，我们提供的遗传证据表明，NFATc 1是必不可少的破骨细胞分化在体内过继转移的NFATc 1（-/-）造血干细胞的破骨细胞缺陷的Fos（-/-）小鼠，并通过Fos（-/-）囊胚互补，从而避免胚胎致死的NFATc 1（-/-）小鼠。然而，在体外破骨细胞生成NFATc 1缺陷的细胞被救出的异位表达NFATc 2。NFATc 1的体内基本作用和NFATc 2的体外作用之间的差异归因于NFAT通过其启动子区域对NFATc 1基因的选择性自动调节。这表明表观遗传机制有助于NFATc 1在细胞谱系定型中的基本功能。因此，本研究确定NFATc 1代表了骨疾病的潜在治疗靶点，并揭示了NFATc 1在骨稳态中的重要作用的机制。
NFATc1 and NFATc2 are functionally redundant in the immune system, but it was suggested that NFATc1 is required exclusively for differentiation of osteoclasts in the skeletal system. Here we provide genetic evidence that NFATc1 is essential for osteoclast differentiation in vivo by adoptive transfer of NFATc1(-/-) hematopoietic stem cells to osteoclast-deficient Fos(-/-) mice, and by Fos(-/-) blastocyst complementation, thus avoiding the embryonic lethality of NFATc1(-/-) mice. However, in vitro osteoclastogenesis in NFATc1-deficient cells was rescued by ectopic expression of NFATc2. The discrepancy between the in vivo essential role of NFATc1 and the in vitro effect of NFATc2 was attributed to selective autoregulation of the NFATc1 gene by NFAT through its promoter region. This suggested that an epigenetic mechanism contributes to the essential function of NFATc1 in cell lineage commitment. Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis.