Plasma and Synovial Fluid VEGF-A and Neuropilin-1 in Knee Osteoarthritis: Associations With Radiographic Severity, Pain Sensitization-Related Features, and Disease Burden.

Abstract

This study aimed to investigate associations of plasma and synovial fluid vascular endothelial growth factor A (VEGF-A) and neuropilin-1 (NRP1) levels with radiographic severity, pain sensitization-related features, and disease burden in knee osteoarthritis (KOA). Plasma VEGF-A and NRP1 were measured by sandwich ELISA in 120 patients with KOA (Kellgren-Lawrence [KL] grade 2, n = 40; grade 3, n = 52; grade 4, n = 28) and 53 healthy controls, while synovial fluid VEGF-A and NRP1 were assessed in the KOA group. Pain sensitization-related features and disease burden were evaluated using the Central Sensitization Inventory (CSI), pressure pain threshold (PPT), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and visual analog scale (VAS). Plasma VEGF-A and NRP1 levels were elevated in KOA patients versus healthy controls and increased with KL grade, while synovial fluid VEGF-A and NRP1 rose with radiographic severity. Synovial fluid VEGF-A showed stronger discriminatory performance for radiographic severity than synovial fluid NRP1. After the Benjamini-Hochberg FDR correction, plasma and synovial fluid VEGF-A/NRP1 remained associated with VAS, WOMAC, CSI-defined symptom burden, and local PPT in the overall KOA cohort. Multivariable regression adjusted for KL grade, age, sex, BMI, and symptom duration showed that synovial fluid VEGF-A had the strongest independent associations with clinical outcomes. Bootstrap-validated combined ROC models, particularly those incorporating VEGF-A, showed good discriminatory performance for KOA status and severity stratification. These findings suggest that the VEGF-A-NRP1 axis, particularly synovial fluid VEGF-A, may serve as a biomarker framework for KOA severity assessment and symptom-related phenotyping.