Our goal was to elucidate microRNAs (miRNAs) that may repress the excess bone morphogenetic protein (BMP) signaling observed during pathological calcification in the Klotho mouse model of kidney disease. We hypothesized that restoring healthy levels of miRNAs that post-transcriptionally repress osteogenic calcific factors may decrease aortic calcification. Our relative abundance profiles of miRNAs in healthy aorta differ greatly from those in calcified mouse aorta. Many of these miRNAs are predicted to regulate proteins involved in BMP signaling and may control osteogenesis. Two differentially regulated miRNAs, miR-145 and miR-378, were selected based on three criteria: reduced levels in calcified aorta, the ability to target more than one protein in the BMP signaling pathway, and conservation of targeted sequences between humans and mice. Forced expression using a lentiviral vector demonstrated that restoring normal levels repressed the synthesis of BMP2 and other pro-osteogenic proteins and inhibited pathological aortic calcification in Klotho mice with renal insufficiency. This study identified miRNAs that may impact BMP signaling in both sexes and demonstrated the efficacy of selected miRNAs in reducing aortic calcification in vivo. Calcification of the aorta and the aortic valve resulting from abnormal osteogenesis is common in those with kidney disease, diabetes, and high cholesterol. Such vascular osteogenesis is a clinically significant feature. The calcification modulating miRNAs described here are candidates for biomarkers and "miRNA replacement therapies" in the context of chronic kidney disease and other pro-calcific conditions.

中文翻译：

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钙化主动脉和健康主动脉中的 MicroRNA 谱存在差异：miR-145 和 miR-378 的治疗影响。


我们的目标是阐明可抑制 Klotho 小鼠肾病模型病理钙化过程中观察到的过量骨形态发生蛋白 (BMP) 信号传导的 microRNA (miRNA)。我们假设，恢复转录后抑制成骨钙化因子的 miRNA 的健康水平可能会减少主动脉钙化。我们的健康主动脉中 miRNA 的相对丰度谱与钙化小鼠主动脉中的 miRNA 相对丰度谱有很大差异。其中许多 miRNA 预计可调节参与 BMP 信号传导的蛋白质，并可能控制骨生成。根据三个标准选择两种差异调节的 miRNA：miR-145 和 miR-378：主动脉钙化水平降低、靶向 BMP 信号通路中一种以上蛋白质的能力以及人类和小鼠之间靶序列的保守性。使用慢病毒载体的强制表达表明，恢复正常水平可以抑制 BMP2 和其他促成骨蛋白的合成，并抑制肾功能不全的 Klotho 小鼠的病理性主动脉钙化。这项研究鉴定了可能影响两性 BMP 信号传导的 miRNA，并证明了所选 miRNA 在减少体内主动脉钙化方面的功效。成骨异常导致的主动脉和主动脉瓣钙化在患有肾病、糖尿病和高胆固醇的患者中很常见。这种血管成骨是临床上的重要特征。这里描述的钙化调节 miRNA 是慢性肾病和其他促钙化疾病背景下生物标志物和“miRNA 替代疗法”的候选者。