Blimp1-mediated repression of negative regulators is required for osteoclast differentiation
Blimp1-mediated repression of negative regulators is required for osteoclast differentiation
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DOI：
10.1073/pnas.0912779107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Nishikaw, Keizo;Nakashima, Tomoki;Takayanagi, Hiroshi
不可逆的细胞谱系定型的调节依赖于正调控因子和负调控因子之间的微妙平衡，这包括复杂的转录因子网络。NF-κ B配体受体激活因子（RANKL）通过诱导活化T细胞核因子c1（NFATc 1）（破骨细胞生成的必需转录因子）刺激骨吸收破骨细胞的分化。破骨细胞特异性的NFATc1的稳健诱导是通过自身放大机制实现的，其中NFATc1通过钙信号传导不断激活，而NFATc1的负调节因子被抑制。然而，目前还不清楚这些负调节因子在破骨细胞生成过程中是如何被抑制的。在此，我们发现破骨细胞生成过程中RANKL通过NFATc 1诱导的B淋巴细胞诱导成熟蛋白1（Blimp 1;由Prdm 1编码）作为抗破骨细胞生成基因（如Irf 8和Maf B b）的转录抑制因子发挥作用。Blimp1的过表达导致破骨细胞形成的增加，而Prdm1缺陷的破骨细胞前体细胞不能有效地进行破骨细胞分化。破骨细胞特异性Prdm 1基因缺陷的小鼠表现出破骨细胞数量减少引起的高骨量表型，这一观察结果强调了Blimp 1在骨稳态中的重要性。因此，NFATc1通过诱导负调节因子的抑制以及通过其对正调节因子的作用来编排破骨细胞谱系中细胞命运的确定。
Regulation of irreversible cell lineage commitment depends on a delicate balance between positive and negative regulators, which comprise a sophisticated network of transcription factors. Receptor activator of NF-kappa B ligand (RANKL) stimulates the differentiation of bone-resorbing osteoclasts through the induction of nuclear factor of activated T cells c1 (NFATc1), the essential transcription factor for osteoclastogenesis. Osteoclast-specific robust induction of NFATc1 is achieved through an autoamplification mechanism, in which NFATc1 is constantly activated by calcium signaling while the negative regulators of NFATc1 are suppressed. However, it has been unclear how such negative regulators are repressed during osteoclastogenesis. Here we show that B lymphocyte-induced maturation protein-1 (Blimp1; encoded by Prdm1), which is induced by RANKL through NFATc1 during osteoclastogenesis, functions as a transcriptional repressor of anti-osteoclastogenic genes such as Irf8 and Mafb. Overexpression of Blimp1 leads to an increase in osteoclast formation, and Prdm1-deficient osteoclast precursor cells do not undergo osteoclast differentiation efficiently. The importance of Blimp1 in bone homeostasis is underscored by the observation that mice with an osteoclast-specific deficiency in the Prdm1 gene exhibit a high bone mass phenotype caused by a decreased number of osteoclasts. Thus, NFATc1 choreographs the determination of cell fate in the osteoclast lineage by inducing the repression of negative regulators as well as through its effect on positive regulators.