Department of Orthopedics, Chengdu Seventh People's Hospital (Tianfu District), Sichuan 610299, China.
Department of Orthopedics, The Sixth Affiliated Hospital of Xinjiang Medical University, Xinjiang 830002, China.
Biomed Res Int. 2022 Jun 15;2022:9093614. doi: 10.1155/2022/9093614. eCollection 2022.
Osteoporosis is a widespread bone disease that affects million cases annually. The underlying mechanisms behind the progress of osteoporosis remain enigmatic, which limits detections of biomarkers and therapeutic targets. Hence, this study was aimed at exploring hub molecules to better understand the mechanism of osteoporosis development and discover the traditional Chinese medicine potential drugs for osteoporosis. miRNA and gene expression profiles were downloaded from Gene Expression Omnibus (GEO). Weighted correlation network analysis (WGCNA) was used to identify the key modules for osteoporosis. DIANA Tools was applied to perform pathway enrichment. A miRNA-gene interaction network was constructed, and hub miRNAs and genes were distinguished using Cytoscape software. Receiver operating characteristic (ROC) curves of hub miRNAs and genes were plotted, and correlations with hub genes and osteoporosis-associated factors were evaluated. Potential drugs for osteoporosis in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) were screened, and molecular docking models between these drugs and target genes were showed by AutoDock tools. Two hub modules, 1 miRNA module and 1 gene module, were identified to be the most strongly correlated with osteoporosis by using WGCNA. Then, 3 KEGG pathways including focal adhesion, PI3K-Akt signaling pathway, and gap junction were shared pathways enriched with the miRNAs and genes screened out by WGCNA and differential expression analyses. Finally, after constructing a miRNA-gene interaction network, 6 hub miRNAs (hsa-miR-18b-3p, hsa-miR-361-3p, hsa-miR-484, hsa-miR-519e-5p, hsa-miR-940, and hsa-miR-1275) and 6 hub genes (THBS1, IFNAR2, ARHGAP5, TUBB2B, FLNC, and NTF3) were detected. ROC curves showed good performances of miRNAs and genes for osteoporosis. Correlations with hub genes and osteoporosis-associated factors suggested implicational roles of them for osteoporosis. Based on these hub genes, 3 natural compounds (kainic acid, uridine, and quercetin), which were the active ingredients of 192 herbs, were screened out, and a target-compound-herb network was extracted using TCMSP. Molecular docking models of kainic acid-NTF3, uridine-IFNAR2, and quercetin-THBS1 were exhibited with AutoDock tools. Our study sheds light on the pathogenesis of osteoporosis and provides promising therapeutic targets and traditional Chinese medicine drugs for osteoporosis.
骨质疏松症是一种广泛存在的骨骼疾病，每年影响着数以百万计的病例。骨质疏松症进展背后的潜在机制仍然是个谜，这限制了生物标志物和治疗靶点的检测。因此，本研究旨在探索枢纽分子，以更好地理解骨质疏松症发展的机制，并发现骨质疏松症的潜在中药治疗药物。从基因表达综合数据库（GEO）下载 miRNA 和基因表达谱。使用加权相关网络分析（WGCNA）识别骨质疏松症的关键模块。应用 DIANA Tools 进行通路富集分析。构建 miRNA-基因互作网络，使用 Cytoscape 软件区分枢纽 miRNA 和基因。绘制枢纽 miRNA 和基因的接收者操作特征（ROC）曲线，并评估与枢纽基因和骨质疏松症相关因素的相关性。从中药系统药理学数据库和分析平台（TCMSP）筛选骨质疏松症的潜在中药治疗药物，并使用 AutoDock 工具展示这些药物与靶基因之间的分子对接模型。通过 WGCNA 确定与骨质疏松症最相关的 2 个枢纽模块，1 个 miRNA 模块和 1 个基因模块。然后，通过 WGCNA 和差异表达分析筛选出的 miRNA 和基因富集了 3 个 KEGG 通路，包括粘着斑、PI3K-Akt 信号通路和缝隙连接。最后，构建 miRNA-基因互作网络后，检测到 6 个枢纽 miRNA（hsa-miR-18b-3p、hsa-miR-361-3p、hsa-miR-484、hsa-miR-519e-5p、hsa-miR-940 和 hsa-miR-1275）和 6 个枢纽基因（THBS1、IFNAR2、ARHGAP5、TUBB2B、FLNC 和 NTF3）。ROC 曲线显示 miRNA 和基因对骨质疏松症具有良好的性能。与枢纽基因和骨质疏松症相关因素的相关性表明它们对骨质疏松症具有暗示作用。基于这些枢纽基因，从 192 种草药的活性成分中筛选出 3 种天然化合物（ kainic acid、uridine 和 quercetin），并使用 TCMSP 提取出靶-化合物-草药网络。使用 AutoDock 工具展示 kainic acid-NTF3、uridine-IFNAR2 和 quercetin-THBS1 的分子对接模型。我们的研究揭示了骨质疏松症的发病机制，并为骨质疏松症提供了有前途的治疗靶点和中药药物。
