Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist
Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist
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DOI：
10.1016/j.prostaglandins.2008.02.001
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发表时间：
2008-06-01
影响因子：
2.9
通讯作者：
Raisz, Lawrence
中科院分区：
文献类型：
--
作者：
Choudhary, Shilpa;Alander, Cynthia;Raisz, Lawrence
使用前列腺素E受体(EP)激动剂的研究表明，前列腺素(PG)E-2可以通过EP4和EP2受体发挥合成代谢作用。我们先前发现，在培养的小鼠颅骨成骨细胞中，选择性EP4受体激动剂(EP4A，Ono Pharmtics)的合成代谢反应显著大于选择性EP2受体激动剂(EP2A)。为了进一步确定EP2受体在PG介导的骨细胞效应中的作用，我们检测了EP2受体缺失(HER)或两者(KO)等位基因缺失的小鼠的头盖骨原代成骨细胞(POB)和骨髓基质细胞(MSC)与野生型(WT)小鼠的作用。实时荧光定量聚合酶链式反应、Western印迹和免疫组织化学检测证实EP2受体缺失。在这些研究中，用于提供细胞的1个月大的小鼠在静态组织形态计量学上没有显示出任何显著的股骨差异。通过碱性磷酸酶mRNA的表达和活性以及骨钙素的mRNA表达和矿化，发现EP2A促进了骨髓和颅骨WT细胞的分化。在Het鼠的培养中，这种影响有所减弱，而在KO鼠的培养中，这种影响被废除。PGE(2)的作用大于EP2A，尤其是在POB细胞培养中，而在HET和KO细胞培养中，PGE(2)的作用仅略有减弱。我们的结论是，EP2受体的激活能够促进成骨细胞的分化，EP2A是该受体的真正选择性激动剂，PGE(2)具有可能由EP4受体介导的额外的合成代谢作用。(C)2008 Elsevier Inc.保留所有权利。
Studies using prostaglandin E receptor (EP) agonists indicate that prostaglandin (PG) E-2 can have anabolic effects through both EP4 and EP2 receptors. We previously found that the anabolic response to a selective EP4 receptor agonist (EP4A, Ono Pharmaceutical) was substantially greater than to a selective EP2 receptor agonist (EP2A) in cultured murine calvarial osteoblastic cells. To further define the role of the EP2 receptor in PG-mediated effects on bone cells, we examined the effects of EP2A and PGE(2) on both calvarial primary osteoblasts (POB) and marrow stromal cells (MSC) cultured from mice with deletion of one (Her) or both (KO) alleles of the EP2 receptor compared to their wild-type (WT) littermates. Deletion of EP2 receptor was confirmed by quantitative real-time PCR, Western blot and immunohistochemistry. The 1 month-old mice used to provide cells in these studies did not show any significant differences in their femurs by static histomorphometry. EP2A was found to enhance osteoblastic differentiation as measured by alkaline phosphatase mRNA expression and activity as well as osteocalcin mRNA expression and mineralization in the WT cell cultures from both marrow and calvariae. The effects were somewhat diminished in cultures from Het mice and abrogated in cultures from KO mice. PGE(2) effects were greater than those of EP2A, particularly in POB cultures and were only moderately diminished in Het and KO cell cultures. We conclude that activation of the EP2 receptor is able to enhance differentiation of osteoblasts, that EP2A is a true selective agonist for this receptor and that PGE(2) has an additional anabolic effect likely mediated by the EP4 receptor. (C) 2008 Elsevier Inc. All rights reserved.