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. 2022 Jul 15;101(28):e29856.
doi: 10.1097/MD.0000000000029856.

Differentially expressed genes and miRNAs in female osteoporosis patients

Hailong Zhou  1 , Jianmin Jiang  2 , Xiaohua Chen  3 , Zhiwei Zhang  3
Affiliations

Differentially expressed genes and miRNAs in female osteoporosis patients

Hailong Zhou et al. Medicine (Baltimore). .

Abstract

Osteoporosis is characterized by lowing bone mineral density. This study aimed to investigate the genes, miRNAs, pathways, and miRNA-gene interaction pairs involved in the pathogenesis of female osteoporosis. The differentially expressed genes (DEGs, GSE62402), differentially expressed miRNAs (DEmiRNAs, GSE63446), and differentially methylated genes (GSE62588) between females with low- and high-hip bone mineral density were identified. Genes common to DEGs, differentially methylated genes, DEmiRNAs' targets, and osteoporosis-related genes were retained and used to construct the miRNA-mRNA-pathway regulatory network. The expression of hub nodes was validated in microarray datasets (genes in GSE56116 and miRNAs in GSE93883). Thirty-four DEmiRNAs and 179 DEGs with opposite expression-methylation profiles were identified. Functional enrichment analysis showed that DEGs were associated with pathways including "hsa00380:Tryptophan metabolism," "hsa04670:Leukocyte transendothelial migration," "hsa04630:Jak-STAT signaling pathway," and "hsa04062:Chemokine signaling pathway." The miRNA-mRNA-pathway network included 10 DEGs, 9 miRNAs, and 4 osteoporosis-related pathways. The miRNA-gene-pathway axes including hsa-miR-27b-5p/3p-IFNAR1-hsa04630, hsa-miR-30a-5p/3p-IFNAR1-hsa04630, hsa-miR-30a-5p/3p-ALDH2-hsa00380, and hsa-miR-194-5p/3p-NCF2-hsa04670 were included in the network. Microarray validation showed that IFNAR1, NCF2, and ALDH2 were upregulated, and hsa-miR-30a-3p/5p, hsa-miR-194-3p/5p, hsa-miR-27b-3p/5p, and hsa-miR-34a-3p were downregulated in osteoporotic samples compared with control. Axes including hsa-miR-27b/30a-IFNAR1-Jak-STAT signaling pathway, hsa-miR-30a-ALDH2-Tryptophan metabolism, and hsa-miR-194-NCF2-Leukocyte transendothelial migration were involved in osteoporosis pathogenesis.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
The flow chart of data analysis in this study. CTD = comparative toxicogenomics database, DEGs = differentially expressed genes, DEmiRNAs = differentially expressed miRNAs, DMG = differentially methylated genes, HMDD = human MicroRNA disease database, OS = osteoporosis.
Figure 2.
Figure 2.
The statistical summary and expression profiles of the differentially expressed themes in datasets. (A) the volcano plots presenting of the DEGs (in the GSE62402 dataset), miRNAs (DEmiRNAs, in the GSE63446 dataset), and genes with DMGs (in the GSE62588 dataset) between the samples with high- and low-hip BMD. Up (right and yellow nodes) and down regulation (left and blue nodes) in the high-BMD group was defined as log2 (FC) >0.5 and log2FC <–0.5, combined by FDR <0.05. (B) The sample heatmap clustering which is constructed based on the profiling of DEGs, DEmiRNAs, and DMGs in the 3 datasets. Up and down regulation is presented by red and blue color, respectively. BMD = bone mineral density, DEGs = differentially expressed genes, DMGs = differentially methylated levels, FC = fold change, FDR = fold discovery rate.
Figure 3.
Figure 3.
The identification of the DEGs with opposite differential methylation levels. (A) The Venn diagram of the DEGs in the GSE62402 dataset and DMGs in the GSE62588 dataset. (B) the 4 elephants figure showing the associations between expression and methylation profiles of the 324 DEGs in Figure 2A. (C) The bubble diagram presenting the Kyoto Encyclopedia of Genes and Genomes pathways associated with cluster II DEGs. The node size and color correspond to the gene number and significance. DEGs = differentially expressed genes, DMGs = differentially methylated levels.
Figure 4.
Figure 4.
The differentially expressed miRNA-mRNA regulatory network. This network consisted of 15 upregulated miRNAs (red triangles) and 87 hypermethylated and downregulated genes (sky blue circles) in the blood samples from females with high-hip BMD compared with females low-hip BMD. BMD = bone mineral density.
Figure 5.
Figure 5.
The miRNA-mRNA-pathway regulatory involving differentially expressed miRNAs and genes. The miRNAs (upregulated in high-BMD group compared with low-hip BMD group, red triangles), genes (downregulated in high-BMD group compared with low-hip BMD group; sky blue circles), and pathways (green, diamonds) are all associated with osteoporosis. “T” lines note the inhibitory regulation of miRNAs on its targets, and arrow lines present the involvement of genes in corresponding pathways. BMD = bone mineral density.
Figure 6.
Figure 6.
The validation of the expression profiles of several genes and miRNAs. (A) the expression profiles of 4 upregulated genes in the peripheral blood samples from OS and control females (GSE93883). (B) The expression profiles of the matured sequences of 6 premature miRNAs in the plasma samples from female with and without osteoporosis. The difference of each gene/miRNA in the patient and control groups was analyzed using the nonparametric Mann-Whitney U test. OS = osteoporosis.
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