Crucial Involvement of the EP4 Subtype of Prostaglandin E Receptor in Osteoclast Formation by Proinflammatory Cytokines and Lipopolysaccharide
Crucial Involvement of the EP4 Subtype of Prostaglandin E Receptor in Osteoclast Formation by Proinflammatory Cytokines and Lipopolysaccharide
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前列腺素 E 受体 EP4 亚型在促炎细胞因子和脂多糖参与破骨细胞形成中的关键作用
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发表时间：
2000
影响因子：
6.2
通讯作者：
K. Nakao
中科院分区：
文献类型：
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作者：
Y. Sakuma;Kiyoshi Tanaka;M. Suda;A. Yasoda;K. Natsui;I. Tanaka;F. Ushikubi;S. Narumiya;E. Segi;Y. Sugimoto;A. Ichikawa;K. Nakao
前列腺素E2 （Prostaglandin E2, PGE2）通过EP1、EP2、EP3、EP4四种亚型的PGE受体发挥作用。在原代成骨细胞（POB）和骨髓细胞共培养中，11‐脱氧- PGE1（一种EP4和EP2激动剂）比丁他前列腺素（一种EP2激动剂）和其他激动剂更能促进破骨细胞的形成，这表明EP4是PGE2诱导的破骨细胞形成的主要因素。EP4缺失（EP4 k/o）小鼠的POB与野生型（w/t）小鼠的脾细胞共培养未观察到PGE2诱导的破骨细胞形成，而w/t小鼠的POB与EP4 k/o小鼠的脾细胞共培养可形成破骨细胞。原位杂交（ISH）结果显示，EP4信使RNA （mRNA）在w/t小鼠成骨细胞上表达，而在多核细胞（MNCs）上不表达。这些结果表明，PGE2通过其EP4亚型对成骨细胞促进破骨细胞的形成。白细胞介素1α （IL‐1α）、肿瘤坏死因子α （TNF‐α）、碱性成纤维细胞生长因子（bFGF）和脂多糖（LPS）在EP4‐k/o小鼠POB细胞和骨髓细胞共培养中几乎没有观察到破骨细胞的形成，这表明PG和EP4亚型在这些分子的破骨细胞形成中起着至关重要的作用。相反，在EP4‐k/o小鼠中，1,25‐羟维生素D3 （1,25(OH)2D3）的破骨细胞形成未受到损害，甲状旁腺激素（PTH）的破骨细胞形成仅部分受损，这可能与EP4‐k/o小鼠未显示明显骨骼异常有关。由于已有研究表明IL - 1α、TNF - α、bFGF和LPS参与炎症性骨质流失，我们的工作有望有助于理解这些疾病的病理生理学。（J Bone Miner Res 2000; 15:218-227）
Prostaglandin E2 (PGE2) exerts its effects through the PGE receptor that consists of four subtypes (EP1, EP2, EP3, and EP4). Osteoclast formation in the coculture of primary osteoblastic cells (POB) and bone marrow cells was enhanced more by 11‐deoxy‐PGE1 (an EP4 and EP2 agonist) than by butaprost (an EP2 agonist) and other agonists, which suggests that EP4 is the main factor in PGE2‐induced osteoclast formation. PGE2‐induced osteoclast formation was not observed in the coculture of POB from EP4‐deficient (EP4 k/o) mice and spleen cells from wild‐type (w/t) mice, whereas osteoclasts were formed in the coculture of POB from w/t mice and spleen cells from EP4‐k/o mice. In situ hybridization (ISH) showed that EP4 messenger RNA (mRNA) was expressed on osteoblastic cells but not on multinucleated cells (MNCs) in w/t mice. These results indicate that PGE2 enhances osteoclast formation through its EP4 subtype on osteoblasts. Osteoclast formation by interleukin 1α (IL‐1α), tumor necrosis factor α (TNF‐α), basic fibroblast growth factor (bFGF), and lipopolysaccharide (LPS) was hardly observed in the coculture of POB and bone marrow cells, both from EP4‐k/o mice, which shows the crucial involvement of PG and the EP4 subtype in osteoclast formation by these molecules. In contrast, osteoclast formation by 1,25‐hydroxyvitamin D3 (1,25(OH)2D3) was not impaired and that by parathyroid hormone (PTH) was only partially impaired in EP4‐k/o mice, which may be related to the fact that EP4‐k/o mice revealed no gross skeletal abnormalities. Because it has been suggested that IL‐1α, TNF‐α, bFGF, and LPS are involved in inflammatory bone loss, our work can be expected to contribute to an understanding of the pathophysiology of these conditions.(J Bone Miner Res 2000;15:218–227)
影响因子：
4.8
作者：
Takehiko Koji;R. Brenner
通讯作者：
Takehiko Koji;R. Brenner
影响因子：
4.1
作者：
Hurley, MM;Lee, SK;Lorenzo, J
通讯作者：
Lorenzo, J
影响因子：
15.9
作者：
AbuAmer, Y;Ross, FP;Teitelbaum, SL
通讯作者：
Teitelbaum, SL