Identification of Two-pore Channel 2 as a Novel Regulator of Osteoclastogenesis*
Identification of Two-pore Channel 2 as a Novel Regulator of Osteoclastogenesis*
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鉴定双孔通道 2 作为破骨细胞生成的新型调节剂*
DOI：
10.1074/jbc.m111.328930
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
M. Noda
中科院分区：
文献类型：
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作者：
T. Notomi;Y. Ezura;M. Noda
背景：双孔通道2（TPC 2）是一种钙离子通道，但其在破骨细胞中的功能尚不清楚。结果：RANKL诱导破骨细胞分化后，破骨细胞前体细胞中TPC 2表达水平增加。TPC 2表达下调抑制RANKL诱导的细胞内Ca 2+信号传导以及NFATc 1的核定位，并抑制破骨细胞生成。结论：TPC 2调控破骨细胞的生成。意义：TPC 2在破骨细胞分化中起关键作用。破骨细胞分化是骨质疏松症中控制骨量水平的关键步骤之一，但破骨细胞生成的分子机制仍不完全清楚。在这里，我们表明，双孔通道2（TPC 2）在破骨细胞前体细胞中表达，其在这些细胞中的敲低（TPC 2-KD）抑制RANKL诱导的关键事件，包括多核化，抗酒石酸酸性磷酸酶（TRAP）活性的增强，和TRAP mRNA表达水平。在细胞内信号传导方面，TPC 2-KD降低了RAW细胞中RANKL诱导的Ca 2+动态波动水平。对TPC 2靶点的研究表明，NFATc 1在TPC 2-KD细胞中的核定位延迟。最后，TPC 2-KD抑制了培养物中骨陷窝的形成。我们的结论是，TPC 2是一个新的破骨细胞生成的关键分子。
Background: Two-pore channel 2 (TPC2) is a calcium channel, but its function in osteoclasts is unknown. Results: TPC2 expression levels in osteoclast precursor cells were increased upon osteoclast differentiation induced by RANKL. Down-regulation of TPC2 expression suppressed RANKL-induced intracellular Ca2+ signaling as well as nuclear localization of NFATc1 and inhibited osteoclastogenesis. Conclusion: TPC2 regulates osteoclastogenesis. Significance: TPC2 plays a critical role in osteoclast differentiation. Osteoclast differentiation is one of the critical steps that control bone mass levels in osteoporosis, but the molecules involved in osteoclastogenesis are still incompletely understood. Here, we show that two-pore channel 2 (TPC2) is expressed in osteoclast precursor cells, and its knockdown (TPC2-KD) in these cells suppressed RANKL-induced key events including multinucleation, enhancement of tartrate-resistant acid phosphatase (TRAP) activities, and TRAP mRNA expression levels. With respect to intracellular signaling, TPC2-KD reduced the levels of the RANKL-induced dynamic waving of Ca2+ in RAW cells. The search for the target of TPC2 identified that nuclear localization of NFATc1 is retarded in TPC2-KD cells. Finally, TPC2-KD suppressed osteoclastic pit formation in cultures. We conclude that TPC2 is a novel critical molecule for osteoclastogenesis.