Sex Differences in Osteoarthritis Pathogenesis: A Comprehensive Study Based on Bioinformatics

Abstract

BACKGROUND Osteoarthritis (OA) is a common disorder in the elderly. OA influences the daily life of patients and has become a worldwide health problem. It is still unclear whether the pathogenesis mechanism is different between males and females. This study investigated the differentially expressed genes (DEGs) and explored the different signaling pathways of OA between males and females. MATERIAL AND METHODS Data sets of GSE55457, GSE55584, and GSE12021 were retrieved from Gene Expression Omnibus to conduct DEGs analysis. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology term was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatics tool. The protein interaction network was constructed in Cytoscape 3.7.2. qRT-PCR was then performed to validate the expression of hub genes in OA patients and healthy people. RESULTS In total, 4 co-upregulated and 10 co-downregulated genes were identified. We found that enriched pathways were different between males and females. BCL2L1, EEF1A1, EEF2, HNRNPD, and PABPN1 were considered as hub genes in OA pathogenesis in males, while EEF2, EEF1A1, RPL37A, FN1 were considered as hub genes in OA pathogenesis in females. Consistent with the bioinformatics analysis, the qRT-PCR analysis also showed that the gene expression of BCL2L1, HNRNPD, and PABPN1 was significantly lower in male OA patients. In contrast, EEF2, EEF1A1, and RPL37A were significantly lower in female OA patients. CONCLUSIONS The DEGs identified may be involved in different OA disease progression mechanisms between males and females, and they are considered as treatment targets or prognosis markers for males and females. The pathogenesis mechanism is sex-dependent.

Figure 1

Heat map of the top 100 DEGs of GSE55457, GSE55584, and GSE12021. Red represents upregulation and blue represents downregulation. (A) Females. (B) Males.

Figure 2

Co-upregulated and downregulated DEGs were calculated by Venn diagram. The intersection of purple (upregulated DEGs in females) and green (upregulated DEGs in males) represents co-upregulated DEGs. The intersection of yellow (downregulated DEGs in females) and pink (downregulated DEGs in males) represents co-downregulated DEGs.

Figure 3

(A) Enrichment analysis results of DEGs in females. (B) Enrichment analysis results of DEGs in males.

Figure 4

PPI network of DEGs in females and males constructed by STRING. (A) Females. (B) Males.

Figure 5

Information on hub genes in females and males. The length of the column represents the value of degree, the size of the bubble represents the value of betweenness, and the color of the bubble represents the value of closeness. (A) Females. (B) Males. Degree represents the association degree of one node and all the other nodes in the network. Closeness is the close degree of a node and other nodes in the network. Betweenness is the number of times that a node acts as the shortest bridge between the other 2 nodes.

Figure 6

Top 50 genes of degree in the PPI network of females and males. The color of the sectors represents the signal-to-noise value. The labels of hub genes are in blue. (A) Females. (B) Males.

Figure 7

Expression of hub genes in men and women. (A) The expression of BCL2L1, HNRNPD, and PABPN1 in OA patients was lower than in normal people in males. (B) The expression of EEF2, EEF1A1, and RPL37A in OA patients was lower than in normal people in females. *** p<0.001.