Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling
Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling
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DOI：
10.1038/sj.emboj.7601430
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发表时间：
2006-12-13
期刊：
影响因子：
11.4
通讯作者：
Kim, Hong-Hee
中科院分区：
文献类型：
--
作者：
Ryu, Jiyoon;Kim, Hyung Joon;Kim, Hong-Hee
1-磷酸鞘氨醇（S1 P）由鞘氨醇激酶（SPHK）产生，通过细胞内和细胞外两种方式发挥作用。我们使用骨髓源性巨噬细胞（BMM）单个和BMM/成骨细胞共培养系统评估SPHK 1和S1 P在破骨细胞生成中的作用。在BMM单一培养物中，破骨细胞生成因子受体活化因子NF-κ B配体（RANKL）上调SPHK 1并增加S1 P的产生和分泌。SPHK 1 siRNA通过调节p38和ERK活性以及NFATc 1和c-Fos水平增强破骨细胞生成，SPHK 1过表达减弱破骨细胞生成。细胞外S1 P在这些培养物中没有作用。这些数据表明，在BMM单一培养物中，响应RANKL产生的细胞内S1 P形成负反馈回路。相比之下，S1 P加入BMM/成骨细胞共培养物中，通过环氧合酶-2和PGE（2）调节增加成骨细胞中的RANKL，大大增加了破骨细胞的生成。S1 P还刺激成骨细胞迁移和存活。还观察到T细胞的RANKL升高和趋化作用。这些结果表明，分泌的S1 P吸引并作用于成骨细胞和T细胞，以增加破骨细胞生成。总之，S1 P在破骨细胞生成调节以及破骨细胞与成骨细胞或T细胞之间的通讯中起重要作用。
Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SPHK), acts both by intracellular and extracellular modes. We evaluated the role of SPHK1 and S1P in osteoclastogenesis using bone marrow-derived macrophage (BMM) single and BMM/osteoblast coculture systems. In BMM single cultures, the osteoclastogenic factor receptor activator of NF-kappa B ligand (RANKL) upregulated SPHK1 and increased S1P production and secretion. SPHK1 siRNA enhanced and SPHK1 overexpression attenuated osteoclastogenesis via modulation of p38 and ERK activities, and NFATc1 and c-Fos levels. Extracellular S1P had no effect in these cultures. These data suggest that intracellular S1P produced in response to RANKL forms a negative feedback loop in BMM single cultures. In contrast, S1P addition to BMM/osteoblast cocultures greatly increased osteoclastogenesis by increasing RANKL in osteoblasts via cyclooxygenase-2 and PGE(2) regulation. S1P also stimulated osteoblast migration and survival. The RANKL elevation and chemotactic effects were also observed with T cells. These results indicate that secreted S1P attracts and acts on osteoblasts and T cells to augment osteoclastogenesis. Taken together, S1P plays an important role in osteoclastogenesis regulation and in communication between osteoclasts and osteoblasts or T cells.