Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice
Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice
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DOI：
10.1074/jbc.m002079200
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发表时间：
2000-06-30
影响因子：
4.8
通讯作者：
Suda, T
中科院分区：
文献类型：
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作者：
Miyaura, C;Inada, M;Suda, T
前列腺素E-2（PGE（2））是一种有效的骨吸收刺激剂。在这项研究中，我们首先阐明了正常ddy小鼠中蛋白激酶A和基质金属蛋白酶（MMPs）诱导参与PGE（2）诱导的骨吸收，然后使用缺乏PGE受体各亚型（EP 1、EP 2、EP 3和EP 4）的小鼠鉴定了介导这种PGE（2）作用的PGE受体亚型。在正常ddy小鼠颅骨培养中，PGE（2）和双丁酰环腺苷酸（Bt（2）cAMP）均刺激骨吸收，并诱导MMP-2和MMP-13等MMP。添加蛋白激酶A抑制剂H89或MMPs抑制剂BB 94可显著抑制PGE诱导的骨吸收活性（2）。在EP 1、EP 2和EP 3基因敲除小鼠的颅骨培养物中，PGE（2）刺激骨吸收的程度与野生型小鼠的颅骨相似。另一方面，在EP 4基因敲除小鼠的颅骨培养物中，发现骨吸收对PGE（2）的显著减少。在EP 4基因敲除小鼠的长骨培养物中也检测到对PGE（2）的骨吸收受损。Bt（2）cAMP在野生型和EP 4基因敲除小鼠中同样极大地刺激了骨吸收。在EP 4基因敲除小鼠的颅骨培养物中，PGE（2）对MMP-2和MMP-13的诱导作用受到极大的损害，但Bt（2）cAMP在野生型和EP 4基因敲除小鼠中对MMP-2和MMP-13的诱导作用相似。这些发现表明，PGE（2）通过cAMP依赖性机制通过EP 4受体刺激骨吸收。
Prostaglandin E-2 (PGE(2)) acts as a potent stimulator of bone resorption. In this study, we first clarified in normal ddy mice the involvement of protein kinase A and induction of matrix metalloproteinases (MMPs) in PGE(2)-induced bone resorption, and then identified PGE receptor subtype(s) mediating this PGE(2) action using mice lacking each subtype (EP1, EP2, EP3, and EP4) of PGE receptor. In calvarial culture obtained from normal ddy mice, both PGE(2) and dibutyryl cyclic AMP (Bt(2)cAMP) stimulated bone resorption and induced MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protein kinase A, H89, or an inhibitor of MMPs, BB94, significantly suppressed bone-resorbing activity induced by PGE(2). In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE(2) stimulated bone resorption to an extent similar to that found in calvaria from the wild-type mice. On the other hand, a marked reduction in bone resorption to PGE(2) was found in the calvarial culture from EP4-knockout mice. The impaired bone resorption to PGE(2) was also detected in long bone cultures from EP4-knockout mice. Bt(2)cAMP greatly stimulated bone resorption similarly in both wild-type and EP4-knockout mice. Induction of MMP-2 and MMP-13 by PGE(2) was greatly impaired in calvarial culture from EP4-knockout mice, but Bt(2)cAMP stimulated MMPs induction similarly in the wild-type and EP4-knockout mice. These findings suggest that PGE(2) stimulates bone resorption by a cAMP-dependent mechanism via the EP4 receptor.