Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis
Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis
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DOI：
10.1074/jbc.m505820200
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发表时间：
2005-09-23
影响因子：
4.8
通讯作者：
Takayanagi, H
中科院分区：
文献类型：
--
作者：
Kim, Y;Sato, K;Takayanagi, H
骨稳态取决于破骨细胞骨吸收和成骨细胞骨形成的协调。 NF-kappa B 配体受体激活剂 (RANKL) 通过激活由活化 T 细胞的关键转录因子核因子 (NFAT) c1 介导的转录程序来诱导破骨细胞分化。免疫受体，包括破骨细胞相关受体 (OSCAR) 和骨髓细胞表达的触发受体 (TREM)-2，构成 RANKL 介导的钙信号激活所需的共刺激信号，从而导致 NFATc1 的激活。然而，免疫受体的表达是否受NFATc1控制仍不清楚。在此，我们证明 OSCAR（而非 TREM-2）的表达在破骨细胞生成过程中上调，并被钙调神经磷酸酶抑制剂 FK506 显着抑制，表明 OSCAR 受 NFATc1 转录调节。 NFATc1 表达导致 OSCAR 启动子激活，并发现 PU.1 和小眼相关转录因子 (MITF) 的共表达进一步增强了 OSCAR 启动子的激活。我们通过染色质免疫沉淀分析和 NFATc1(-/-) 细胞中 OSCAR 和 TREM-2 mRNA 的定量进一步提供 NFATc1 特异性调节 OSCAR 的证据。因此，在破骨细胞生成过程中，OSCAR而不是TREM-2参与了免疫受体-NFATc1途径的正反馈回路。尽管多种免疫受体已被确定为 RANKL 的共刺激分子，但其表达和功能的调节存在差异。这些机制，可能连同其配体对成骨细胞的微妙调节，可能为调节破骨细胞生成以维持骨稳态提供了精致的机制。
Bone homeostasis depends on the coordination of osteoclastic bone resorption and osteoblastic bone formation. Receptor activator of NF-kappa B ligand (RANKL) induces osteoclast differentiation through activating a transcriptional program mediated by the key transcription factor nuclear factor of activated T cells ( NFAT) c1. Immunoreceptors, including osteoclast-associated receptor (OSCAR) and triggering receptor expressed by myeloid cells (TREM)-2, constitute the co-stimulatory signals required for RANKL-mediated activation of calcium signaling, which leads to the activation of NFATc1. However, it remains unknown whether the expression of immunoreceptors are under the control of NFATc1. Here we demonstrate that the expression of OSCAR, but not that of TREM-2, is up-regulated during osteoclastogenesis and markedly suppressed by the calcineurin inhibitor FK506, suggesting that OSCAR is transcriptionally regulated by NFATc1. NFATc1 expression results in the activation of the OSCAR promoter, which was found to be further enhanced by co-expression of PU.1 and microphthalmia-associated transcription factor (MITF). We further provide evidence that NFATc1 specifically regulates OSCAR by chromatin immunoprecipitation assay and quantification of OSCAR and TREM-2 mRNAin NFATc1(-/-) cells. Thus, OSCAR but not TREM-2 is involved in the positive feedback loop of the immunoreceptor-NFATc1 pathway during osteoclastogenesis. Although several immunoreceptors have been identified as co-stimulatory molecules for RANKL, the expression and function are differentially regulated. These mechanisms, possibly together with the delicate regulation of their ligands on osteoblasts, may provide the exquisite machinery for the modulation of osteoclastogenesis in the maintenance of bone homeostasis.