Identification of a novel diagnostic biomarker for osteoarthritis associated with chromatin regulators and its association with immune cell infiltration

Background: Osteoarthritis (OA) is considered to be a common chronic degenerative joint disease characterized by cartilage destruction and extracellular matrix degeneration. However, its specific pathogenesis is still unclear. This study aimed to find a novel diagnostic biomarker for osteoarthritis associated with chromatin regulators (CRs) and analyze possible associations between signature genes and immune cell infiltration. Methods: OA datasets were downloaded from the Gene Expression Omnibus (GEO) database and integrated them with the CRs dataset to create a new dataset. Differentially expressed genes (DEGs) associated with CRs were obtained by differential expression analysis, and functional enrichment analysis of these genes was performed. The CRs-related hub genes were further identified by protein-protein interaction (PPI) analysis. The infiltration level of immune cells in OA was analyzed by Single-sample GSEA (ssGSEA) to explore the correlation between the expression level of hub genes and immune infiltration, and the potential targeted therapeutic drugs of hub genes were predicted by Drug SIGnatures DataBase (DSigDB). Hub genes were used to construct OA diagnostic risk model, identify OA diagnostic biomarkers, and verify its diagnostic value by ROC curve and correction curve. Finally, signature genes were validated in vitro and in vivo by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting (WB), and mouse models of destabilization of the medial meniscus (DMM). Results: A total of 86 CRs-related DEGs were obtained. These DEGs were enriched in the histone binding and modification, cell cycle, and FoxO signaling pathways. After PPI analysis, we obtained 10 CRs-related hub genes, and finally determined Aurora kinase B (AURKB) as a diagnostic biomarker for OA by constructing a OA risk prediction model. In mouse DMM models and IL-β-induced chondrocytes, qRT-PCR and WB results showed significantly high expression of AURKB in diseased joints and cells. Moreover, ssGSEA analysis showed that there were significant differences in the infiltration levels of 11 immune cells and 12 immune infiltrating functions in the OA samples. Infiltration analysis of immune cells showed that AURKB expression was positively correlated with tumor infiltrating lymphocyte (TIL), Th1 cells, T cell co-inhibition and check-point. Finally, based on the obtained 10 CRs-related hub genes, we found that dasatinib, enterolactone and genistein may be potential targeted therapies for OA. Conclusion: Overall, our study shows that AURKB is an important biomarker in the development and progression of OA and is significantly correlated with immune infiltration, providing a new way to explore the pathogenesis of OA.