OBJECTIVE: Osteoarthritis (OA) is a prevalent degenerative joint disease, especially occur in the elderly. This study aimed to uncover a novel biomarker for early diagnosis and treatment of OA. METHODS: WGCNA, differential expression analysis and PPI network were used for screening hub genes-related to OA, utilizing the GSE55235 and GSE57218 datasets from GEO database. RESULTS: Based on the data in the GEO datasets, compared to normal tissues, ITGB5 was obviously elevated in OA cartilage and synovial samples. Additionally, ROC curve results validated the diagnostic value of ITGB5 in OA. Mechanistically, transcription factors KLF4 and KLF11 could modulate ITGB5 gene transcription via binding to its promoter region, thereby affecting ITGB5 gene expression in OA tissues. GSEA results showed that ITGB5 gene was closely related to p53, wnt, TNF and T cell receptor signaling pathways, suggesting that ITGB5 may play potential roles in affecting cell apoptosis and inflammation in OA. Moreover, ITGB5 levels in OA samples was positively correlated to T helper type 1 cells, natural killer T cells, macrophages, memory CD8 T cells, activated dendritic cells. CONCLUSION: In this study, we found that ITGB5 was obviously elevated in OA samples. Moreover, ITGB5 may function as a diagnostic biomarker in OA.