Qiao Yanchun, Li Jie, Liu Dandan, Zhang Chenying, Liu Yang, Zheng Shuguo
Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, Beijing, China.
Front Genet. 2023 Jan 6;13:1072948. doi: 10.3389/fgene.2022.1072948. eCollection 2022.
Osteoporosis (OP) is a severe systemic bone metabolic disease that occurs worldwide. During the coronavirus pandemic, prioritization of urgent services and delay of elective care attenuated routine screening and monitoring of OP patients. There is an urgent need for novel and effective screening diagnostic biomarkers that require minimal technical and time investments. Several studies have indicated that N6-methyladenosine (m6A) regulators play essential roles in metabolic diseases, including OP. The aim of this study was to identify key m6A regulators as biomarkers of OP through gene expression data analysis and experimental verification. GSE56815 dataset was served as the training dataset for 40 women with high bone mineral density (BMD) and 40 women with low BMD. The expression levels of 14 major m6A regulators were analyzed to screen for differentially expressed m6A regulators in the two groups. The impact of m6A modification on bone metabolism microenvironment characteristics was explored, including osteoblast-related and osteoclast-related gene sets. Most m6A regulators and bone metabolism-related gene sets were dysregulated in the low-BMD samples, and their relationship was also tightly linked. In addition, consensus cluster analysis was performed, and two distinct m6A modification patterns were identified in the low-BMD samples. Subsequently, by univariate and multivariate logistic regression analyses, we identified four key m6A regulators, namely, , , , and . We built a diagnostic model based on the four m6A regulators. and were protective factors, whereas and were risk factors, and the ROC curve and test dataset validated that this model had moderate accuracy in distinguishing high- and low-BMD samples. Furthermore, a regulatory network was constructed of the four hub m6A regulators and 26 m6A target bone metabolism-related genes, which enhanced our understanding of the regulatory mechanisms of m6A modification in OP. Finally, the expression of the four key m6A regulators was validated and , which is consistent with the bioinformatic analysis results. Our findings identified four key m6A regulators that are essential for bone metabolism and have specific diagnostic value in OP. These modules could be used as biomarkers of OP in the future.
骨质疏松症（OP）是一种在全球范围内发生的严重全身性骨代谢疾病。在新冠疫情期间，紧急服务的优先安排和择期护理的延迟削弱了对OP患者的常规筛查和监测。迫切需要新型且有效的筛查诊断生物标志物，其所需的技术和时间投入最少。多项研究表明，N6-甲基腺苷（m6A）调节剂在包括OP在内的代谢性疾病中起重要作用。本研究的目的是通过基因表达数据分析和实验验证，确定关键的m6A调节剂作为OP的生物标志物。GSE56815数据集用作40名高骨密度（BMD）女性和40名低BMD女性的训练数据集。分析了14种主要m6A调节剂的表达水平，以筛选两组中差异表达的m6A调节剂。探讨了m6A修饰对骨代谢微环境特征的影响，包括成骨细胞相关和破骨细胞相关基因集。大多数m6A调节剂和骨代谢相关基因集在低BMD样本中失调，它们之间的关系也紧密相连。此外，进行了一致性聚类分析，在低BMD样本中确定了两种不同的m6A修饰模式。随后，通过单变量和多变量逻辑回归分析，我们确定了四个关键的m6A调节剂，即 、 、 和 。我们基于这四个m6A调节剂建立了一个诊断模型。 和 是保护因素，而 和 是风险因素，ROC曲线和测试数据集验证了该模型在区分高BMD和低BMD样本方面具有中等准确性。此外，构建了一个由四个核心m6A调节剂和26个m6A靶标骨代谢相关基因组成的调控网络，这加深了我们对OP中m6A修饰调控机制的理解。最后，在 和 中验证了四个关键m6A调节剂的表达，这与生物信息学分析结果一致。我们的研究结果确定了四个对骨代谢至关重要且在OP中具有特定诊断价值的关键m6A调节剂。这些模块未来可用作OP的生物标志物。
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