Sphingosine-1-phosphate/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation and thereby induces Runx2 expression in osteoblasts
Sphingosine-1-phosphate/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation and thereby induces Runx2 expression in osteoblasts
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DOI：
10.1016/j.bone.2016.09.003
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发表时间：
2016-12-01
期刊：
影响因子：
4.1
通讯作者：
Nishimura, Fusanori
中科院分区：
文献类型：
--
作者：
Higashi, Katsumasa;Matsuzaki, Etsuko;Nishimura, Fusanori
鞘氨醇-L-磷酸是一种信号转导鞘磷脂，在骨再生中也发挥着重要作用。最近，我们报道了S1PR1和S1PR2受体主要在成骨样细胞中表达，S1P/S1PR1信号通路上调了骨保护素和成骨细胞的分化。然而，S1P/S1PR2信号在成骨细胞分化中的作用还不是很清楚。在这里，我们研究了S1P/S1PR2介导的信号在成骨细胞分化中的作用，并阐明了潜在的信号机制。我们发现S1P/S1PR2/GI非依赖的信号通路激活了RhoA活性，导致小鼠成骨样MOT3-E1细胞和原代成骨细胞中Smad1/5/8的磷酸化。此外，该信号通路促进了Smad4的核转位，并增加了Smad6/7蛋白在细胞核中的含量。SIP还通过S1PR2/RhoA/ROCK/Smad1/5/8信号上调矮小相关转录因子2(Runx2)的表达。此外，我们还发现，在体内，SIP部分触发了S1PR2/RhoA/ROCK通路，导致骨形成。这些结果表明，SIP诱导RhoA活性，导致Smad1/5/8的磷酸化，从而促进成骨细胞中Runx2的表达和分化。我们的发现描述了S1P/S1PR2介导的成骨细胞分化的新的分子机制，这可能有助于未来的骨再生研究。(C)2016 Elsevier Inc.保留所有权利。
Sphingosine-l-phosphate (SIP) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the SIP receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MOT3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. SIP also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that SIP partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo. These findings suggest that SIP induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration. (C) 2016 Elsevier Inc. All rights reserved.