Extracorporeal Shock Wave Therapy in Knee Osteoarthritis: A Mechanistic Narrative Review of Neurogenic Inflammation and the MMP/ADAMTS Axis.

Knee osteoarthritis (KOA) is a whole-joint disorder in which structural degeneration interacts with synovial inflammation, peripheral nociceptive sensitization, and the local neuroimmune microenvironment. Extracorporeal shock wave therapy (ESWT) improves pain and function in many clinical studies, but its disease-modifying potential remains uncertain. This narrative review integrates clinical and experimental evidence on two candidate mechanisms: suppression of neurogenic inflammation and regulation of the protease-inhibitor network formed by matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteases, and tissue inhibitors of metalloproteinases (TIMPs). The most consistent human evidence supports symptomatic benefit. Mechanistically, ESWT may reduce sensory nerve excitability, substance P and calcitonin gene-related peptide signaling, and neuroimmune feedback, thereby attenuating peripheral sensitization and synovial inflammation. Preclinical studies also report changes in inflammatory and oxidative-stress mediators, MMP expression, TIMP balance, and ADAMTS-related aggrecan degradation. However, evidence for structural cartilage regeneration is derived mainly from animal models, small biomarker studies, and heterogeneous protocols; long-term human imaging evidence is scarce. Shared interleukin-1β, tumor necrosis factor-α, nuclear factor-κB, and mitogen-activated protein kinase signaling provides a plausible interface between neuroimmune amplification and matrix catabolism. Overall, ESWT is best viewed as a parameter-dependent mechanobiological intervention with supported analgesic effects and plausible, but unconfirmed, matrix-modulatory activity. Standardized protocols, longitudinal biomarker and imaging studies, and pathway-directed experiments are needed before ESWT can be considered a disease-modifying therapy for KOA.