Prostaglandin receptor EP4 mediates the bone anabolic effects of PGE2
Prostaglandin receptor EP4 mediates the bone anabolic effects of PGE2
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DOI：
10.1124/mol.60.1.36
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发表时间：
2001-07-01
影响因子：
3.6
通讯作者：
Rodan, GA
中科院分区：
文献类型：
--
作者：
Machwate, M;Harada, S;Rodan, GA
前列腺素（PG）E-2是人类和动物中皮质骨和松质骨形成的有效诱导剂。虽然PGE（2）的骨合成代谢作用已被充分证实，但介导这种作用的细胞和分子机制仍不清楚。本研究旨在研究前列腺素受体EP 4（PGE（2）受体之一）的药理学失活对PGE（2）诱导的体内骨形成的影响。我们首先确定了EP（4）A（一种EP 4选择性配体）作为拮抗剂的能力。PGE（2）增加RP-1骨膜细胞系的细胞内cAMP并抑制细胞凋亡。这两种作用都被EP（4）A逆转，表明EP（4）A在与其体外结合EP 4的浓度一致的情况下在细胞中作为EP 4拮抗剂发挥作用。然后，我们研究了EP 4对PGE（2）诱导的幼鼠骨形成的影响。在存在或不存在EP（4）A（10 mg/kg/天）的情况下，用PGE（2）（6 mg/kg/天）处理5至6周龄大鼠12天。我们发现EP（4）A治疗可抑制PGE（2）诱导的骨小梁体积增加。这种效应伴随着骨形成指数的抑制：血清骨钙素、标记表面的范围和小梁数量的范围，表明骨体积的减少最有可能是由于骨形成减少。本研究提供的药理学证据有力地支持了PGE（2）在大鼠中的骨合成代谢作用是由EP 4受体介导的这一假设。
Prostagtandin (PG) E-2 is a potent inducer of cortical and trabecular bone formation in humans and animals. Although the bone anabolic action of PGE(2) is well documented, the cellular and molecular mechanisms that mediate this effect remain unclear. This study was undertaken to examine the effect of pharmacological inactivation of the prostanoid receptor EP4, one of the PGE(2) receptors, on PGE(2)-induced boneformation in vive. We first determined the ability of EP(4)A, an EP4-selective ligand, to act as an antagonist. PGE(2) increases intracellular cAMP and suppresses apoptosis in the RP-1 periosteal cell line. Both effects were reversed by EP(4)A, suggesting that EP(4)A acts as an EP4 antagonist in the cells at concentrations consistent with its in vitro binding to EP4. We then examined the effect of EP4 on bone formation induced by PGE(2) in young rats. Five- to 6-week-old rats were treated with PGE(2) (6 mg/kg/day) in the presence or absence of EP(4)A (10 mg/kg/day) for 12 days. We found that treatment with EP(4)A suppresses the increase in trabecular bone volume induced by PGE(2). This effect is accompanied by a suppression of bone formation indices: serum osteocalcin, extent of labeled surface, and extent of trabecular number, suggesting that the reduction in bone volume is due most likely to decreased bone formation. The pharmacological evidence presented here provides strong support for the hypothesis that the bone anabolic effect of PGE(2) in rats is mediated by the EP4 receptor.