Sex differences in the pathogenesis of degenerative knee osteoarthritis: a comparative transcriptomics analysis

Osteoarthritis (OA) is one of the leading diseases worldwide and is expected to continue to rise in prevalence. Epidemiological studies on OA have long shown a sex discrepancy between males and females, with females consistently showing greater rates of OA. There are numerous theories about why this might be the case; however, the discrepancy is still poorly understood.

In this study, two cohorts of patients with Kellgren-Lawrence grade IV knee OA were grouped based on sex and analyzed to decipher transcriptomic differences. The first cohort was a GSE114007 public dataset from the NCBI Gene Expression Omnibus (GEO) database, while the second cohort was from our institution. For each cohort, differential gene expression analysis (DEG), principal component analysis (PCA), functional enrichment analyses (Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis, and Gene Ontology), and protein-protein interaction (PPI) analysis were performed.

In the GSE114007 cohort, XIST gene was the sole significant DEG at the genome-wide level. In contrast, our local cohort showed 109 DEGs between males and females. Functional enrichment analyses in both the GSE114007 and local cohorts showed female upregulation of inflammatory pathways, while the local cohort also showed female increases in protein synthesis and metabolic pathways, with males showing greater enrichment of structural and tissue remodeling pathways. PPI analysis showed female upregulation of three clusters of interacting proteins related to protein synthesis and translation, energy metabolism, oxidative phosphorylation, cell communication, and tissue remodeling.

Our analyses suggest that the pathogenesis of OA in women may be related to inflammatory and metabolic mechanisms, whereas OA in men may be driven by structural pathways involved in stress and remodeling. Hence, sex specific therapeutic strategies may be necessary to effectively target the pathobiological mechanisms driving OA in males and females.