RANKL-mediated Reactive Oxygen Species Pathway That Induces Long Lasting Ca2+ Oscillations Essential for Osteoclastogenesis
RANKL-mediated Reactive Oxygen Species Pathway That Induces Long Lasting Ca2+ Oscillations Essential for Osteoclastogenesis
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DOI：
10.1074/jbc.m109.051557
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发表时间：
2010-03-05
影响因子：
4.8
通讯作者：
Shin, Dong Min
中科院分区：
文献类型：
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作者：
Kim, Min Seuk;Yang, Yu-Mi;Shin, Dong Min
RANKL（NF-κ B配体受体激活剂）通过激活破骨细胞前体细胞中的多种信号传导途径诱导破骨细胞生成，其中主要是诱导细胞内Ca 2+浓度（[Ca 2 +]（i））的长期振荡。[Ca 2 +]（i）振荡激活钙调磷酸酶，钙调磷酸酶激活转录因子NFATc 1。RANKL诱导[Ca 2 +]（i）振荡和破骨细胞生成的途径尚不清楚。在这里，我们报告了RANKL诱导的一种新途径的发现，该途径可导致活性氧自由基（ROS）和[Ca 2 +]（i）振荡的长期持续增加，这对于骨髓源性单核细胞分化为破骨细胞至关重要。该途径包括RANKL介导的刺激Rac 1产生ROS，ROS刺激磷脂酶C γ 1通过刺激1，4，5-三磷酸肌醇池中的Ca 2+释放和STIM 1调节的Ca 2+内流来诱发[Ca 2 +]（i）振荡。仅在RANKL刺激24小时后观察到该通路的诱导和激活，并持续至少3天。该途径的生理作用在缺失Peroxiredoxin II基因的小鼠中得到证实，并导致ROS显著增加，从而导致骨密度降低。此外，骨髓来源的单核细胞在PrxII（-/-）原代培养物中显示增加的ROS和自发的[Ca 2 +]（i）振荡。这些发现确定了触发破骨细胞生成晚期和调节骨吸收的主要RANKL刺激途径。
RANKL (receptor activator of NF-kappa B ligand) induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca2+ ([Ca2+](i)). The [Ca2+](i) oscillations activate calcineurin, which activates the transcription factor NFATc1. The pathway by which RANKL induces [Ca2+](i) oscillations and osteoclastogenesis is poorly understood. Here we report the discovery of a novel pathway induced by RANKL to cause a long lasting increase in reactive oxygen species (ROS) and [Ca2+](i) oscillations that is essential for differentiation of bone marrow-derived monocytes into osteoclasts. The pathway includes RANKL-mediated stimulation of Rac1 to generate ROS, which stimulate phospholipase C gamma 1 to evoke [Ca2+](i) oscillations by stimulating Ca2+ release from the inositol 1,4,5-trisphosphate pool and STIM1-regulated Ca2+ influx. Induction and activation of the pathway is observed only after 24-h stimulation with RANKL and lasts for at least 3 days. The physiological role of the pathway is demonstrated in mice with deletion of the Peroxiredoxin II gene and results in a mark increase is ROS and, consequently, a decrease in bone density. Moreover, bone marrow-derived monocytes in PrxII(-/-) primary culture show increased ROS and spontaneous [Ca2+](i) oscillations. These findings identify the primary RANKL-stimulated pathway to trigger the late stages of osteoclastogenesis and regulate bone resorption.