Immune heterogeneity-driven therapeutic responses to platelet-rich plasma and TRPV1 antagonism in osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) exhibits substantial heterogeneity in synovial immune profiles, which may underlie variable analgesic responses to standard biological and neuromodulatory treatments. Remodeling the immune microenvironment while targeting nociceptive pathways may improve therapeutic consistency. METHODS: Analgesic efficacy of platelet-rich plasma (PRP) combined with transient receptor potential vanilloid 1 (TRPV1) antagonism was evaluated in a monosodium iodoacetate (MIA)-induced rat OA model. Synovial immune polarization, inflammatory signaling, peripheral and central sensitization were assessed mechanistically. Clinical outcomes were analyzed in a cohort of 140 OA patients receiving combination or single-agent therapy. RESULTS: Combined PRP and TRPV1 blockade produced stronger analgesia than either treatment alone in rats. The combination shifted synovial macrophages toward an anti-inflammatory M2 phenotype, suppressed NF-κB signaling, and reduced pro-inflammatory cytokines. It also decreased dorsal root ganglion excitability and spinal glial activation, indicating reduced peripheral and central sensitization. In OA patients, combination therapy yielded superior pain relief, functional improvement, and reduced sensitization-related phenotypes. DISCUSSION: These findings support a neuroimmune model in which synovial immune heterogeneity influences treatment responsiveness. Concurrent immune remodeling via PRP and nociceptor inhibition via TRPV1 antagonism represents a promising strategy to achieve more reliable analgesia in OA.