Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells In Vitro
Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells In Vitro
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DOI：
10.1002/jbmr.2897
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发表时间：
2016-12-01
影响因子：
6.2
通讯作者：
Link, Thomas M.
中科院分区：
文献类型：
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作者：
Heilmeier, Ursula;Hackl, Matthias;Link, Thomas M.
标准的DXA测量，包括骨折风险评估工具（FRAX）评分，在评估2型糖尿病（T2D）的骨折风险方面显示出局限性，强调了对新型生物标志物的需求，并提示其他病理机制可能导致糖尿病骨脆性。MicroRNAs （miRNAs）从各种组织的细胞分泌到循环中，与局部疾病的严重程度成正比，最近发现对骨稳态和T2D至关重要。在本研究中，我们研究了在糖尿病骨病和绝经后骨质疏松症（80名绝经后妇女）中，循环miRNAs或miRNAs组合是否以及哪些miRNAs可以区分最佳骨折状态。然后，我们在体外测试了最具歧视性和最常见的mirna。使用mirna - qpcr阵列，我们发现48种mirna可以区分T2D女性的骨折状态，并且四种mirna的几种组合可以以高特异性和敏感性区分糖尿病相关骨折（受体工作特征曲线值下面积[auc]， 0.92至0.96;95% CI， 0.88至0.98）。在骨质疏松研究组，23个mirna是骨折指示性的，4个mirna的潜在组合auc为0.97 ~ 1.00 （95% CI, 0.93 ~ 1.00）。由于在所有miRNA组合中最具区别性和最常见的miRNA在骨稳态中的作用尚未被描述，我们在人脂肪组织来源的间充质干细胞中进行了体外功能研究，以研究miR-550a-5p、miR-188-3p和miR-382-3p对成骨、脂肪形成和细胞增殖的影响。我们发现miR-382-3p显著促进成骨分化(p
Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well-characterized study of diabetic bone disease and postmenopausal osteoporosis (n=80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA-qPCR-arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes-related fractures with high specificity and sensitivity (area under the receiver-operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture-indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue-derived mesenchymal stem cells to investigate the effect of miR-550a-5p, miR-188-3p, and miR-382-3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR-382-3p significantly enhanced osteogenic differentiation (p