Cyclooxygenase-2 expression and prostaglandin E2 production in response to acidic pH through OGR1 in a human osteoblastic cell line
Cyclooxygenase-2 expression and prostaglandin E2 production in response to acidic pH through OGR1 in a human osteoblastic cell line
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DOI：
10.1359/jbmr.080236
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发表时间：
2008-07-01
影响因子：
6.2
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Tomura, Hideaki;Wang, Ju-Qiang;Okajima, Fumikazu
酸中毒已被证明会导致体内骨钙的流失。这种钙释放过程被认为部分是细胞介导的。在骨器官培养中，酸性pH已被证明可以诱导环氧合酶-2 （COX-2）的诱导和前列腺素E-2 （PGE(2)）的产生，从而刺激骨钙的释放。然而，成骨细胞感知酸性环境从而诱导COX-2诱导和PGE(2)产生的分子机制尚不清楚。在这项研究中，我们使用人类成骨细胞系（NHOst）来表征细胞活性，包括肌醇磷酸产生、细胞内Ca2+浓度（[Ca2+](i)）、PGE(2)产生和COX-2 mRNA和蛋白表达，以响应细胞外酸化。OGR1受体特异性小干扰RNA （siRNA）和细胞内信号通路特异性抑制剂被用来表征酸化诱导的细胞活动。我们发现细胞外酸性PH诱导细胞内[Ca2+](i)和肌醇磷酸生产的短暂增加。酸化也诱导了COX-2的诱导，导致PGE(2)的产生。这些质子诱导的作用被靶向OGR1受体的siRNA和G（q/11）蛋白、磷脂酶C和蛋白激酶C的抑制剂显著抑制。我们得出结论，OGR1/G(q/11)/磷脂酶C/蛋白激酶C通路调节成骨细胞COX-2的诱导和随后的PGE(2)的产生，以应对酸性环境。
Acidosis has been shown to induce depletion of bone calcium from the body. This calcium release process is thought to be partially cell mediated. In an organ culture of bone, acidic pH has been shown to induce cyclooxygenase-2 (COX-2) induction and prostaglandin E-2 (PGE(2)) production, resulting in stimulation of bone calcium release. However, the molecular mechanisms whereby osteoblasts sense acidic circumstances and thereby induce COX-2 induction and PGE(2) production remain unknown. In this study, we used a human osteoblastic cell line (NHOst) to characterize cellular activities, including inositol phosphate production, intracellular Ca2+ concentration ([Ca2+](i)), PGE(2) production, and COX-2 mRNA and protein expression, in response to extracellular acidification. Small interfering RNA (siRNA) specific to the OGR1 receptor and specific inhibitors for intracellular signaling pathways were used to characterize acidification-induced cellular activities. We found that extracellular acidic PH induced a transient increase in [Ca2+](i) and inositol phosphate production in the cells. Acidification also induced COX-2 induction, resulting in PGE(2) production. These proton-induced actions were markedly inhibited by siRNA targeted for the OGR1 receptor and the inhibitors for G(q/11) protein, phospholipase C, and protein kinase C. We conclude that the OGR1/G(q/11)/phospholipase C/protein kinase C pathway regulates osteoblastic COX-2 induction and subsequent PGE(2) production in response to acidic circumstances.