Neuropeptide Y signaling in osteoarthritis pain: neuroimmune mechanisms, joint remodeling, and translational opportunities.

Osteoarthritis is a leading cause of chronic musculoskeletal pain, but pain severity is not fully explained by cartilage loss or radiographic damage. Neuropeptide Y is a multifunctional neuropeptide with receptor- and compartment-dependent effects on nociceptive signaling, sympathetic activity, immune regulation, and skeletal remodeling. Direct osteoarthritis-specific evidence links synovial-fluid neuropeptide Y to pain in some human knee osteoarthritis cohorts, NPY2R signaling to chondrocyte hypertrophy and matrix catabolism, and osteocyte-derived neuropeptide Y to experimental osteoarthritis remodeling. By contrast, proposed effects on synovial fibroblast phenotypes, macrophage polarization, central sensitization, and gut-joint communication are supported mainly by mechanistically adjacent non-osteoarthritis models and remain hypothesis-generating. This review synthesizes current evidence with a pain-centered and translational focus, emphasizing receptor specificity, evidence source, and disease context. Neuropeptide Y is best viewed as one candidate node within broader nociceptive, inflammatory, vascular, metabolic, and biomechanical networks rather than as a primary or exclusive driver of osteoarthritis. Translation will require receptor-selective and tissue-selective strategies, local delivery systems, validated multi-marker panels, and phenotype-stratified studies that distinguish pain-related from structure-related effects.