Prostaglandin E2 receptors EP2 and EP4 are down-regulated during differentiation of mouse osteoclasts from their precursors
Prostaglandin E2 receptors EP2 and EP4 are down-regulated during differentiation of mouse osteoclasts from their precursors
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DOI：
10.1074/jbc.m500926200
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发表时间：
2005-06-24
影响因子：
4.8
通讯作者：
Takahashi, N
中科院分区：
文献类型：
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作者：
Kobayashi, Y;Take, I;Takahashi, N
前列腺素E-2（PGE（2））是一种有效的骨吸收刺激剂。然而，PGE 2本身已被证明直接抑制破骨细胞的骨吸收活性。我们研究了PGE 2在体外形成的小鼠破骨细胞功能中的作用。骨髓巨噬细胞破骨细胞前体细胞表达PGE 2受体EP 1、EP 2、EP 3 β和EP 4，在NF-κ B受体激活剂配体和巨噬细胞集落刺激因子诱导的破骨细胞分化过程中，EP 2和EP 4的表达下调。相反，功能性EP 1在成熟破骨细胞中持续表达。前列腺素E2和降钙素引起破骨细胞内钙内流。然而，PGE（2）和17-phenyltrinol-PGE（2）（一种EP 1激动剂）不能抑制在牙本质切片上培养的破骨细胞的肌动蛋白环形成和小窝形成。当使用携带EP 4 cDNA的腺病毒在破骨细胞中表达EP 4时，破骨细胞的肌动蛋白环和陷窝形成活性以感染单位依赖的方式被抑制。用PGE 2处理表达EP 4的破骨细胞进一步抑制其肌动蛋白环和陷窝形成活性。EP 4介导的信号对破骨细胞功能的这种抑制作用类似于降钙素受体介导的那些。因此，破骨细胞前体细胞在分化为破骨细胞的过程中下调其自身的EP 2和EP 4水平，以逃避PGE（2）对骨吸收的抑制作用。
Prostaglandin E-2 (PGE(2)) has been proposed to be a potent stimulator of bone resorption. However, PGE2 itself has been shown to directly inhibit bone-resorbing activity of osteoclasts. We examined the role of PGE2 in the function of mouse osteoclasts formed in vitro. Bone marrow macrophage osteoclast precursors expressed PGE2 receptors EP1, EP2, EP3 beta, and EP4, and the expression of EP2 and EP4 was down-regulated during osteoclastic differentiation induced by receptor activator of NF-kappa B ligand and macrophage colony-stimulating factor. In contrast, functional EP1 was continuously expressed in mature osteoclasts. PGE2 as well as calcitonin caused intracellular Ca2+ influx in osteoclasts. However, PGE(2) and 17-phenyltrinol-PGE(2) (an EP1 agonist) failed to inhibit actin- ring formation and pit formation by osteoclasts cultured on dentine slices. When EP4 was expressed in osteoclasts using an adenovirus carrying EP4 cDNA, both actin-ring and pit-forming activities of osteoclasts were inhibited in an infectious unit-dependent manner. Treatment of EP4-expressing osteoclasts with PGE2 further inhibited their actin- ring and pit-forming activities. Such inhibitory effects of EP4-mediated signals on osteoclast function are similar to those that are calcitonin receptor-mediated. Thus, osteoclast precursors down-regulate their own EP2 and EP4 levels during their differentiation into osteoclasts to escape inhibitory effects of PGE(2) on bone resorption.