Abnormalities in osteoclastogenesis and decreased tumorigenesis in mice deficient for ovarian cancer G protein-coupled receptor 1.
Abnormalities in osteoclastogenesis and decreased tumorigenesis in mice deficient for ovarian cancer G protein-coupled receptor 1.
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DOI：
10.1371/journal.pone.0005705
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发表时间：
2009-05-28
期刊：
影响因子：
3.7
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Li H;Wang D;Singh LS;Berk M;Tan H;Zhao Z;Steinmetz R;Kirmani K;Wei G;Xu Y
卵巢癌G蛋白偶联受体1（OGR 1）已被证明是体外质子敏感受体。我们已经证明，OGR 1作为一个肿瘤转移抑制基因，当它在体内的人前列腺癌细胞中过表达。为了研究OGR 1的生理功能，我们通过同源重组产生了条件性OGR 1缺陷小鼠。OGR 1缺陷小鼠存活，肉眼检查显示正常。与显示OGR 1参与破骨细胞生成的体外研究一致，在OGR 1缺陷小鼠中检测到破骨细胞减少。还观察到pH依赖性破骨细胞存活效应。然而，未观察到这些动物骨骼的总体异常。此外，在OGR 1缺陷小鼠中，黑色素瘤细胞肿瘤发生被显著抑制。当用巯基乙酸盐刺激时，混合背景中的OGR 1缺陷小鼠产生显著较少的腹膜巨噬细胞。这些巨噬细胞也显示出改变细胞外信号调节激酶（ERK）的激活和一氧化氮（NO）的生产响应脂多糖。在巨噬细胞或棕色脂肪细胞中未观察到通过cAMP产生和细胞存活评估的OGR 1依赖性pH反应，推测是由于这些细胞中存在其他质子感应受体。我们的研究结果表明，OGR 1在破骨细胞生成中的作用不足以影响整体骨发育，其在肿瘤发生中的作用值得进一步研究。所产生的小鼠可能用于几种疾病模型，包括癌症或破骨细胞相关疾病。
Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo. To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice. A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate. These macrophages also showed altered extracellular signal-regulated kinases (ERK) activation and nitric oxide (NO) production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells. Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases.