Deficiency of DGCR8 increases bone formation through dpwnregulation of miR-22 expression
Deficiency of DGCR8 increases bone formation through dpwnregulation of miR-22 expression
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DOI：
10.1016/j.bone.2017.07.021
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发表时间：
2017-10-01
期刊：
影响因子：
4.1
通讯作者：
Cho, Je-Yoel
中科院分区：
文献类型：
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作者：
Choi, Young-Jin;Jeong, Sujin;Cho, Je-Yoel
微小RNA（microRNA，miRNA）通过转录后调节基因表达，对骨形成有重要作用。成熟的miRNA在DROSHA/DGCR 8和DICER连续切割后产生。然而，最近的研究已经确定，一些miRNA只需要这些酶中的一种。大多数试图阐明miRNA在骨形成过程中的作用的研究都是使用DICER缺失策略进行的，但对DGCR 8的作用知之甚少。为了研究DGCR 8在骨生成中的功能，我们通过Collal-Cre产生了骨祖细胞中Dgcr 8条件性缺失的小鼠。Dgcr 8-cK 0小鼠显示股骨中骨体积（Bwrv）、骨小梁数量（Tb/N）和骨小梁厚度（Tb.Th）增加，但骨小梁分离（Tb.Sp）减少。Von Kossa、抗酒石酸酸性磷酸酶染色和钙黄绿素双标记鉴定Dgcr 8-cK 0小鼠中成骨细胞活性增加。为了阐明详细的细胞机制，我们发现miR-22在Dgcr 8-cK 0小鼠中下调，导致成骨细胞的关键标志物骨钙素转录物上调。有趣的是，在成骨细胞分化过程中，Dgcr 8的mRNA表达水平下降。综上所述，这些结果强烈表明，DGCR 8依赖性的miR-22生成对于骨形成是必不可少的，并且miR-22可能是患有骨病的个体的治疗靶点。(C)2017爱思唯尔公司All rights reserved.
MicroRNAs (miRNA) significantly contribute to bone formation by post-transcriptional regulation of gene expression. Mature miRNAs are generated following sequential cleavage by DROSHA/DGCR8 and DICER. However, recent studies have identified that some miRNAs require only one of these enzymes. Most studies seeking to clarify the role of miRNA during bone formation have been performed using DICER deletion strategies, but little is known regarding the role of DGCR8. To study the function of DGCR8 in osteogenesis, we generated mice in which Dgcr8 is conditionally deleted in osteoprogenitor cells by Collal-Cre. Dgcr8-cK0 mice showed increased bone volume (Bwrv), trabecular number (Tb/N), and trabecular thickness (Tb.Th), but decreased trabecular separation (Tb.Sp) in the femur. Von Kossa, tartrate-resistant acid phosphatase staining, and calcein double labeling identified that osteoblast activity is increased in Dgcr8-cK0 mice. In an effort to elucidate a detailed cellular mechanism, we found that miR-22 was downregulated in Dgcr8-cK0 mice, leading to upregulation of the osteocalcin transcript, a key marker of osteoblasts. Interestingly, the mRNA expression level of Dgcr8 was decreased during osteoblast differentiation. Taken together, these results strongly indicate that DGCR8-dependent generation of miR-22 is essential for bone formation and that miR-22 could be a therapeutic target for individuals with bone disease. (C) 2017 Elsevier Inc. All rights reserved.