The Proteomic Profiling of a Platelet-Enriched Fraction Identifies an Inflammatory and Immune-Related Signature Associated with Non-Response to Treatment with Plasma Rich in Growth Factors in Knee Osteoarthritis

Background: The use of plasma rich in growth factors (PRGF) is a promising regenerative treatment for knee osteoarthritis (OA), but clinical response is heterogeneous. This study aimed to identify molecular features and explore clinical factors associated with PRGF non-response and explore potential biomarkers for patient stratification. Methods: One hundred patients with knee OA (Kellgren–Lawrence II–III) treated with two intra-articular PRGF injections were evaluated at baseline and 6 months. Clinical response was defined by a ≥8-point improvement in overall knee injury and osteoarthritis outcome score (KOOS). Exploratory proteomic profiling was performed in a subgroup of 33 patients (13 responders and 20 non-responders) using platelet-rich plasma-derived platelet lysate (PRP-PL) generated from the same blood-derived preparation used for treatment. Samples were analyzed by data-independent acquisition mass spectrometry, followed by a bioinformatic analysis of differential proteins and enriched pathways. To further investigate selected proteomic findings, IgA levels were quantified in PRP-PL from the entire cohort. Results: Responders showed significant improvements in pain, overall KOOS, and functional outcomes. Proteomic analysis identified a non-responder signature characterized by increased immunoglobulin chains, complement-related proteins, acute-phase molecules, extracellular matrix remodeling proteins, and metabolic stress markers. Functional enrichment revealed the activation of immune, inflammatory, and tissue remodeling pathways. IgA levels in PRP-PL were significantly higher in non-responders, consistent with the immunoglobulin-related proteomic findings. Conclusions: PRGF non-response is associated with an inflammatory and immune-related phenotype. Higher IgA levels in PRP-PL were associated with reduced treatment responsiveness and may help identify a biological phenotype less likely to benefit from PRGF treatment.