Serum levels of EphA2 are elevated in knee osteoarthritis and associated with disease severity

Wenbin Qian^1*Maping Xiao²Lei Ji²Shuang Feng²

• ¹Department of Sports Medicine, Nantong Rehabilitation Hospital, Nantong 226002, Jiangsu Province, China., Nantong City, China
• ²Department of Orthopedics, Nantong Rehabilitation Hospital, Nantong 226002, Jiangsu Province, China., Nantong, China

Background: This study investigated the clinical relevance of serum ephrin type-A receptor 2 (EphA2) in patients with knee osteoarthritis (OA) compared to healthy controls and its association with disease severity, inflammatory markers, oxidative stress, and cartilage metabolism. Methods: A total of 258 participants, including 138 patients with primary knee OA and 120 age- and sex-matched healthy controls, were recruited between January 2023 and December 2024. OA severity was assessed using the Kellgren-Lawrence grading system, and clinical symptoms were assessed using the WOMAC score. Statistical analyses included group comparisons, Pearson correlations with Benjamini-Hochberg FDR adjustment, ROC curves for diagnostic performance, and multivariate logistic regression to identify independent risk factors. Results: Among patients with knee OA, those with Kellgren-Lawrence (K-L) grade III–IV had significantly higher EphA2 levels than those with K-L grades I–II. Receiver operating characteristic (ROC) analysis determined an optimal EphA2 cut-off of 276.8 pg/mL, yielding 92% sensitivity, 72% specificity, and an AUC of 0.924. After false discovery rate (FDR) correction, EphA2 remained positively correlated with the WOMAC score (r = 0.363, q < 0.003), ESR (r = 0.251, q < 0.006), TNF-α (r = 0.213, q < 0.012), MDA (r = 0.238, q < 0.009), COMP (r = 0.208, q < 0.018), MMP-13 (r = 0.200, q < 0.021), IL-6 (r = 0.198, q < 0.024), and ACSL4 (r = 0.200, q < 0.021). Consistently, serum EphA2 levels showed strong associations with cartilage degradation markers (COMP, HA, MMP-13, and CTX-2), inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17A), oxidative stress (MDA), and ferroptosis (ACSL4), while displaying negative correlations with cartilage synthesis markers (PIICP and aggrecan) and antioxidant defenses (GSH and GPX4). Multivariate logistic regression further identified EphA2 (OR = 1.019, 95% CI: 1.009-1.029, P < 0.001), WOMAC, and TNF-α as independent risk factors for poor prognosis in knee OA. Conclusion: These findings suggest that EphA2 is closely associated with cartilage degradation, inflammation, oxidative stress, and ferroptosis in knee OA and may serve as a promising biomarker for disease diagnosis and progression monitoring.