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JTE013 通过增加囊泡转运、Wnt/Ca 和 BMP/Smad 信号来抑制鞘氨醇-1-磷酸受体 2，从而促进成骨作用。

Inhibition of Sphingosine-1-Phosphate Receptor 2 by JTE013 Promoted Osteogenesis by Increasing Vesicle Trafficking, Wnt/Ca, and BMP/Smad Signaling.

机构信息

Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

出版信息

Int J Mol Sci. 2021 Nov 8;22(21):12060. doi: 10.3390/ijms222112060.

DOI:10.3390/ijms222112060
PMID:34769490
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8584480/
Abstract

Sphingosine-1-phosphate receptor 2 (S1PR2) is a G protein-coupled receptor that regulates various immune responses. Herein, we determine the effects of a S1PR2 antagonist (JTE013) or a S1PR2 shRNA on osteogenesis by culturing murine bone marrow stromal cells (BMSCs) in osteogenic media with JTE013, dimethylsulfoxide (DMSO), a S1PR2 shRNA, or a control shRNA. Treatment with JTE013 or the S1PR2 shRNA increased alkaline phosphatase and alizarin red s staining, and enhanced alkaline phosphatase, RUNX2, osteocalcin, and osterix mRNA levels in BMSCs compared with the controls. Protein analysis revealed that a high dose of JTE013 (4 or 8 μM) increased vesicle trafficking-associated proteins (F-actin, clathrin, Early Endosome Antigen 1 (EEA1), and syntaxin 6) and Wnt/Ca2+ signaling. On the other hand, a low dose of JTE013 (1 to 2 μM) increased BMP/Smad signaling. In contrast, the S1PR2 shRNA reduced vesicle trafficking-associated proteins and attenuated Wnts and BMP/Smad signaling, but enhanced p-CaMKII compared with the control, suggesting that the S1PR2 shRNA influenced osteogenesis via different signaling pathways. Moreover, inhibiting protein trafficking by brefeldin A in BMSCs suppressed Wnts and BMPRs expressions. These data supported that enhanced osteogenesis in JTE013-treated BMSCs is associated with increased vesicle trafficking, which promotes the synthesis and transport of osteogenic protein and matrix vesicles and enhances matrix mineralization.

摘要

鞘氨醇-1-磷酸受体 2（S1PR2）是一种 G 蛋白偶联受体，可调节各种免疫反应。在此，我们通过在成骨培养基中培养鼠骨髓基质细胞（BMSCs），来确定 S1PR2 拮抗剂（JTE013）或 S1PR2 shRNA 对成骨的影响，成骨培养基中含有 JTE013、二甲亚砜（DMSO）、S1PR2 shRNA 或对照 shRNA。与对照组相比，JTE013 或 S1PR2 shRNA 处理增加了碱性磷酸酶和茜素红 s 染色，并增强了 BMSCs 中的碱性磷酸酶、RUNX2、骨钙素和骨桥蛋白 mRNA 水平。蛋白分析显示，高剂量 JTE013（4 或 8 μM）增加了囊泡转运相关蛋白（F-肌动蛋白、网格蛋白、早期内体抗原 1（EEA1）和突触素 6）和 Wnt/Ca2+信号。另一方面，低剂量 JTE013（1 至 2 μM）增加了 BMP/Smad 信号。相反，S1PR2 shRNA 减少了囊泡转运相关蛋白，并减弱了 Wnts 和 BMP/Smad 信号，但与对照组相比，p-CaMKII 增强，表明 S1PR2 shRNA 通过不同的信号通路影响成骨。此外，在 BMSCs 中用布雷菲德菌素 A 抑制蛋白转运抑制了 Wnts 和 BMPRs 的表达。这些数据表明，JTE013 处理的 BMSCs 中增强的成骨作用与囊泡转运增加有关，这促进了成骨蛋白和基质囊泡的合成和转运，并增强了基质矿化。

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