RANKL-induced TRPV2 expression regulates osteoclastogenesis via calcium oscillations
RANKL-induced TRPV2 expression regulates osteoclastogenesis via calcium oscillations
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DOI：
10.1016/j.ceca.2010.09.010
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发表时间：
2010-11-01
期刊：
影响因子：
4
通讯作者：
Okabe, Koji
中科院分区：
文献类型：
--
作者：
Kajiya, Hiroshi;Okamoto, Fujio;Okabe, Koji
核因子kappaB受体激活剂配体(RANKL)在破骨细胞分化(破骨细胞生成)过程中诱导钙振荡并激活活化T细胞核因子1(NFATc1)。Ca~(2+)振荡是破骨细胞发生的重要触发信号，然而，为Ca~(2+)振荡服务的Ca~(2+)通透性内流途径的分子基础尚未确定。利用DNA芯片，我们发现RANKL处理的RAW264.7细胞(破骨前细胞)与未处理的细胞相比，瞬时受体电位香草样通道2(TRPV2)显著表达。因此，我们进一步研究了TRPV2在钙离子振荡和破骨细胞生成中的表达和功能作用。我们发现RANKL主要上调破骨前细胞TRPV2的表达，并以时间依赖的方式引起自发的钙振荡和瞬时的内向阳离子电流。TRPV抑制剂Ru红和四环素诱导的TRPV2沉默显著降低RANKL处理的破骨前细胞的钙振荡频率和瞬时内向电流。沉默钙库操作的钙进入(SOCE)蛋白类似地抑制RANKL诱导的破骨前细胞的振荡和电流。此外，抑制TRPV2也减少了RANKL诱导的NAFTc1的表达、其核转位和破骨细胞的形成。综上所述，破骨前细胞内的钙振荡是由RANKL依赖的TRPV2和SOCE激活以及细胞内钙释放触发的。随后NFATc1的激活促进了破骨细胞的形成。(C)2010爱思唯尔有限公司。保留所有权利。
The receptor activator of NF kappa B ligand (RANKL) induces Ca2+ oscillations and activates the Nuclear Factor of Activated T cells 1 (NFATc1) during osteoclast differentiation (osteoclastogenesis). Ca2+ oscillations are an important trigger signal for osteoclastogenesis, however the molecular basis of Ca2+ permeable influx pathways serving Ca2+ oscillations has not yet been identified. Using a DNA microarray, we found that Transient Receptor Potential Vanilloid channels 2 (TRPV2) are expressed significantly in RANKL-treated RAW264.7 cells (preosteoclasts) compared to untreated cells. Therefore, we further investigated the expression and functional role of TRPV2 on Ca2+ oscillations and osteoclastogenesis. We found that RANKL dominantly up-regulates TRPV2 expression in preosteoclasts, and evokes spontaneous Ca2+ oscillations and a transient inward cation current in a time-dependent manner. TRPV inhibitor ruthenium red and tetracycline-induced TRPV2 silencing significantly decreased both the frequency of Ca2+ oscillations and the transient inward currents in RANKL-treated preosteoclasts. Silencing of store-operated Ca2+ entry (SOCE) proteins similarly suppressed both RANKL-induced oscillations and currents in preosteoclasts. Furthermore, suppression of TRPV2 also reduced RANKL-induced NAFTc1 expression, its nuclear translocation, and osteoclastogenesis. In summary, Ca2+ oscillations in preosteoclasts are triggered by RANKL-dependent TRPV2 and SOCE activation and intracellular Ca2+ release. Subsequent activation of NFATc1 promotes osteoclastogenesis. (C) 2010 Elsevier Ltd. All rights reserved.