Sphingosine-1-Phosphate Modulates the Effect of Estrogen in Human Osteoblasts.
Sphingosine-1-Phosphate Modulates the Effect of Estrogen in Human Osteoblasts.
复制标题
DOI：
10.1002/jbm4.10037
复制
发表时间：
2018-07
期刊：
影响因子：
3.8
通讯作者：
Robinson LJ
中科院分区：
文献类型：
--
作者：
Tantikanlayaporn D;Tourkova IL;Larrouture Q;Luo J;Piyachaturawat P;Witt MR;Blair HC;Robinson LJ
在许多雌激素应答细胞中，鞘氨醇- 1 -磷酸（S1P）的产生与17β -雌二醇（E2）活性有关；在骨发育中，S1P的作用尚不清楚。研究了S1P对人成骨细胞（hOB）增殖和分化的影响。10 nM E2、1 μM S1P或1 μM S1P受体1 （S1PR1）激动剂SEW2871在24小时时均能增加hOB的增殖。s1pr1、2和3 mrna由hOB表达，而S1PR4或S1PR5不表达。S1PR2的表达在分化第7天和第14天增加，与成骨细胞相关mrna一致。E2或S1P可使增殖hOB中S1PR1的表达增加，而S1PR2 mRNA在增殖细胞中不受影响；S1PR3不受E2或S1P的影响。用sphingosine kinase inhibitor （Ski）抑制SPHK活性可显著降低E2的增殖作用。E2和S1P均能在hOB 24小时增加SPHK mRNA。S1P通过激活MAP激酶活性促进成骨细胞增殖。在S1P荧光试验中，E2或S1P均可增加S1P的合成。S1P处理后E2受体mRNA的上调表明E2和S1P信号的相互作用。E2和S1P也能促进碱性磷酸酶的表达。在成骨细胞分化过程中，S1P增加了骨特异性mrna，与E2的作用相似。然而，E2和S1P在某些成骨细胞通路的激活上表现出差异。基因表达阵列的通路分析与成骨细胞分化通路的调控一致；以Rho/Rac小GTPase信号和Map激酶或信号转导和转录激活因子（Stat）中间体为中心的胶原蛋白和细胞粘附蛋白。转录激活还包括S1P或E2显著增加超氧化物歧化酶1和2的转录。我们证明SPHK系统是成骨细胞增殖和分化的协同介质，主要但不完全补充E2，其作用是由S1PR1和S1PR2介导的。©2018作者JBMR Plus由Wiley期刊公司代表美国骨与矿物研究协会出版。
Production of sphingosine‐1‐phosphate (S1P) is linked to 17β‐estradiol (E2) activity in many estrogen‐responsive cells; in bone development, the role of S1P is unclear. We studied effects of S1P on proliferation and differentiation of human osteoblasts (hOB). Ten nM E2, 1 μM S1P, or 1 μM of the S1P receptor 1 (S1PR1) agonist SEW2871 increased hOB proliferation at 24 hours. S1PR 1, 2, and 3 mRNAs are expressed by hOB but not S1PR4 or S1PR5. Expression of S1PR2 was increased at 7 and 14 days of differentiation, in correspondence with osteoblast‐related mRNAs. Expression of S1PR1 was increased by E2 or S1P in proliferating hOB, whereas S1PR2 mRNA was unaffected in proliferating cells; S1PR3 was not affected by E2 or S1P. Inhibiting sphingosine kinase (SPHK) activity with sphingosine kinase inhibitor (Ski) greatly reduced the E2 proliferative effect. Both E2 and S1P increased SPHK mRNA at 24 hours in hOB. S1P promoted osteoblast proliferation via activating MAP kinase activity. Either E2 or S1P increased S1P synthesis in a fluorescent S1P assay. Interaction of E2 and S1P signaling was indicated by upregulation of E2 receptor mRNA after S1P treatment. E2 and S1P also promoted alkaline phosphatase expression. During osteoblast differentiation, S1P increased bone‐specific mRNAs, similarly to the effects of E2. However, E2 and S1P showed differences in the activation of some osteoblast pathways. Pathway analysis by gene expression arrays was consistent with regulation of pathways of osteoblast differentiation; collagen and cell adhesion proteins centered on Rho/Rac small GTPase signaling and Map kinase or signal transducer and activator of transcription (Stat) intermediates. Transcriptional activation also included significant increases in superoxide dismutase 1 and 2 transcription by either S1P or E2. We demonstrate that the SPHK system is a co‐mediator for osteoblast proliferation and differentiation, which is mainly, but not entirely, complementary to E2, whose effects are mediated by S1PR1 and S1PR2. © 2018 The Authors JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.