PGE2 signal through EP2 promotes the growth of articular chondrocytes
PGE2 signal through EP2 promotes the growth of articular chondrocytes
复制标题
DOI：
10.1359/jbmr.041122
复制
发表时间：
2005-03-01
影响因子：
6.2
通讯作者：
Toguchida, J
中科院分区：
文献类型：
--
作者：
Aoyama, T;Liang, BJ;Toguchida, J
EP2是在关节软骨中表达的主要PGE2受体。EP2激动剂增加关节软骨细胞内cAMP，刺激单层和3D培养中的DNA合成。因此，EP2激动剂可能是一种有效的退行性软骨疾病的治疗药物。简介：前列腺素E2(PGE2)通过四种类型的受体EPI-4在不同类型的组织中发挥多效性作用。材料和方法：采用免疫组织化学和RT-PCR方法检测各EP在关节软骨细胞中的表达。从P53-/-小鼠关节软骨建立软骨细胞系MMA2，分析激动剂对每种EP的作用。寻找PGE2信号下游的分子。采用基因芯片技术制备EP2激动剂。在大鼠股骨器官培养中检测EP2激动剂对软骨基质包裹的软骨细胞的促生长作用。结果与结论：EP2是关节软骨中主要表达的EP。用每种EP的特定激动剂处理MMA2细胞显示，只有EP2激动剂以剂量依赖的方式显著增加细胞内cAMP水平。MMA2的基因表达谱揭示了一组受EP2激动剂上调的基因，包括几个促进生长和保护细胞凋亡的基因，如细胞周期蛋白D1、纤维连接蛋白、整合素α5、AP2α和14-3-3伽马基因。定量信使核糖核酸分析证实，EP2激动剂上调了人关节软骨细胞中这些基因的表达。在EP2激动剂作用下，人关节软骨细胞5-溴-2-脱氧尿嘧啶(BrdU)掺入增加，大鼠股骨器官培养显示软骨基质包裹的关节软骨细胞增殖细胞核抗原(增殖细胞核抗原)染色增加，提示PGE2信号通过EP2在关节软骨中发挥促生长作用。这些结果表明，PGE2信号。通过EP2促进关节软骨细胞的生长，EP2激动剂有望成为治疗退行性软骨疾病的新的治疗药物。
EP2,was identified as the major PGE2 receptor expressed in articular cartilage. An EP2 agonist increased intracellular cAMP in articular chondrocytes, stimulating DNA synthesis in both monolayer and 3D cultures. Hence, the EP2 agonist may be a potent therapeutic agent for degenerative cartilage diseases.Introduction: Prostaglandin E2 (PGE2) exhibits pleiotropic effects in various types of tissue through four types of receptors, EPI-4. We examined the expression of EPs and effects of agonists for each EP on articular chondrocytes.Materials and Methods: The expression of each EP in articular chondrocytes was examined by immunohistochernistry and RT-PCR. A chondrocyte cell line, MMA2, was established from articular cartilage of p53-/- mice and used to analyze the effects of agonists for each EP. A search for molecules downstream of the PGE2 signal through. the EP2 agonist was made by cDNA microarray analysis. The growth-promoting effect of the EP2 agonist on chondrocytes surrounded by cartilage matrix was examined in an organ culture of rat femora.Results and Conclusion: EP2 was identified as the major EP expressed in articular cartilage. Treatment of MMA2 cells with specific agonists for each EP showed that only the EP2 agonist significantly increased intracellular cAMP levels in a dose-dependent manner. Gene expression profiling of MMA2 revealed a set of genes upregulated by the EP2 agonist, including several growth-promoting and apoptosis-protecting genes such as the cyclin D1, fibronectin, integrin alpha5, AP2alpha, and 14-3-3gamma genes. The upregulation of these genes by the EP2 agonist was confirmed in human articular chondrocytes by quantitative mRNA analysis. On treatment with the EP2 agonist, human articular chondrocytes showed an increase in the incorporation of 5-bromo-2-deoxyuracil (BrdU), and the organ culture of rat femora showed an increase of proliferating cell nuclear antigen (PCNA) staining in articular chondrocytes surrounded by cartilage matrix, suggesting growth-promoting effects of the PGE2 signal through EP2 in articular cartilage. These results suggested that the PGE2 signal. through EP2 enhances the growth of articular chondrocytes, and the EP2 agonist is a candidate for a new therapeutic compound for the treatment of degenerative cartilage diseases.