Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts.
Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts.
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DOI：
10.1371/journal.pone.0020780
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhao M
中科院分区：
文献类型：
--
作者：
Zhang R;Edwards JR;Ko SY;Dong S;Liu H;Oyajobi BO;Papasian C;Deng HW;Zhao M
甲状旁腺激素（PTH）的间歇性应用已在啮齿动物和人类中对骨量产生了良好的合成代谢作用。虽然负责这些作用的转录机制尚未完全理解，但已认识到转录因子cAMP反应元件结合蛋白（CREB）介导成骨细胞中的PTH信号传导，并且PTH-CREB通路和BMP 2信号传导通路之间存在通信，这对于成骨细胞分化和骨形成是重要的。结合BMP 2启动子中的cAMP反应元件（克雷斯），这些发现使我们假设PTH-CREB通路可能是成骨细胞中BMP 2转录的正调节因子。为了验证这一假设，我们首先证明了PTH信号通过成骨细胞中的磷酸化激活CREB，并且PTH和CREB都能够促进原代小鼠成骨细胞和多种啮齿动物成骨细胞系的成骨分化。重要的是，我们发现PTH-CREB信号通路作为BMP 2表达的有效激活剂发挥作用，因为PTH-CREB活性的药理学和遗传调节显著影响这些细胞中BMP 2的表达水平。最后，通过多种启动子检测，包括启动子报告基因缺失、突变、染色质免疫沉淀（ChIP）和电泳迁移率变动分析（EMSA），我们确定了BMP 2启动子中的一个特异性CRE，它负责CREB反式激活成骨细胞中的BMP 2基因。总之，这些结果表明，骨中PTH信号传导的合成代谢功能至少部分地由成骨细胞中BMP 2表达的CREB反式激活介导。
Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts.
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