Sphingosine-1-Phosphate Receptor 2 Controls Podosome Components Induced by RANKL Affecting Osteoclastogenesis and Bone Resorption
Sphingosine-1-Phosphate Receptor 2 Controls Podosome Components Induced by RANKL Affecting Osteoclastogenesis and Bone Resorption
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DOI：
10.3390/cells8010017
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发表时间：
2019-01-01
期刊：
影响因子：
6
通讯作者：
Yu, Hong
中科院分区：
文献类型：
--
作者：
Hsu, Li-Chien;Reddy, Sakamuri, V;Yu, Hong
促炎细胞因子的产生、细胞趋化性和破骨细胞生成可导致炎性骨质流失。此前，我们发现 1-磷酸鞘氨醇受体 2 (S1PR2)（一种 G 蛋白偶联受体）可调节炎症细胞因子的产生和破骨细胞生成。然而，S1PR2 在调节炎症性骨质流失中所调节的信号通路尚未阐明。在此，我们证明，通过特定的 S1PR2 拮抗剂 (JTE013) 抑制 S1PR2 可抑制由口腔细菌病原体、放线菌聚集菌诱导的磷酸肌醇 3 激酶 (PI3K)、丝裂原激活蛋白激酶 (MAPK) 和核因子 κ-B (NF-κ B)，并抑制 IL-1 β、IL-6、TNF-α、和小鼠骨髓细胞中的S1P。此外，S1PR2 的 shRNA 敲低或 JTE013 的处理抑制了细菌刺激的细胞培养基诱导的细胞趋化性。此外，JTE013 在小鼠骨髓培养物中抑制 RANKL 诱导的破骨细胞生成和骨吸收。 ShRNA 敲低 S1PR2 或 JTE013 抑制 S1PR2 可抑制小鼠骨髓细胞中 RANKL 诱导的足小体成分，包括 PI3K、Src、Pyk2、整合素 beta(3)、丝状肌动蛋白 (F-肌动蛋白) 和桩蛋白水平。我们得出结论，S1PR2 在调节促炎细胞因子的产生、细胞趋化性、破骨细胞生成和骨吸收中发挥重要作用。抑制 S1PR2 信号传导可能是治疗与骨骼疾病相关的骨质流失的一种新策略。
Proinflammatory cytokine production, cell chemotaxis, and osteoclastogenesis can lead to inflammatory bone loss. Previously, we showed that sphingosine-1-phosphate receptor 2 (S1PR2), a G protein coupled receptor, regulates inflammatory cytokine production and osteoclastogenesis. However, the signaling pathways regulated by S1PR2 in modulating inflammatory bone loss have not been elucidated. Herein, we demonstrated that inhibition of S1PR2 by a specific S1PR2 antagonist (JTE013) suppressed phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-B (NF-kappa B) induced by an oral bacterial pathogen, Aggregatibacter actinomycetemcomitans, and inhibited the release of IL-1 beta, IL-6, TNF-alpha, and S1P in murine bone marrow cells. In addition, shRNA knockdown of S1PR2 or treatment by JTE013 suppressed cell chemotaxis induced by bacteria-stimulated cell culture media. Furthermore, JTE013 suppressed osteoclastogenesis and bone resorption induced by RANKL in murine bone marrow cultures. ShRNA knockdown of S1PR2 or inhibition of S1PR2 by JTE013 suppressed podosome components, including PI3K, Src, Pyk2, integrin beta(3), filamentous actin (F-actin), and paxillin levels induced by RANKL in murine bone marrow cells. We conclude that S1PR2 plays an essential role in modulating proinflammatory cytokine production, cell chemotaxis, osteoclastogenesis, and bone resorption. Inhibition of S1PR2 signaling could be a novel therapeutic strategy for bone loss associated with skeletal diseases.