Mechanistic insights into cartilage-sensory nerve crosstalk in osteoarthritis progression.

UNLABELLED: Osteoarthritis (OA) pain arises from dynamic crosstalk between degraded cartilage and sensitized sensory nerves. Cartilage-derived signals, including nerve growth factor (NGF), pro-inflammatory cytokines, and matrix-degrading enzymes, promote nerve sprouting and hyperexcitability. While sensory afferents release neuropeptides that further amplify inflammation and cartilage degeneration. Altered joint mechanics additionally activate mechanosensitive ion channels, linking biomechanical stress to nociceptive signaling. This review summarizes current knowledge on cartilage-sensory nerve interactions in OA and their contribution to pain progression. We discuss key molecular mediators, biomarkers, and therapeutic targets, and provide an overview of in vivo, in vitro, and ex vivo model platforms for studying cartilage-sensory nerve crosstalk, highlighting emerging predictive systems for mechanistic and translational research. Together, these insights support the development of mechanism-based pain phenotyping and personalized therapeutic strategies for OA.

CORE TAKE-HOME MESSAGES AND CLINICAL SIGNIFICANCE: •Cartilage actively contributes to OA pain by engaging in bidirectional crosstalk with sensory nerves.•Inflammatory mediators, neuropeptides, and mechanosensitive ion channels form an integrated network driving OA pain.•Predictive in vitro and ex vivo models provide tractable platforms to study cartilage-sensory nerve crosstalk and support translational pain research.•Mechanism-linked neural, inflammatory and mechanosensitive biomarkers enable OA pain phenotyping beyond structural severity.

THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This review highlights cartilage-sensory nerve crosstalk as a key mechanism underlying osteoarthritis pain, moving beyond a structure-centric view of disease progression. Mechanistic insights into neuroinflammatory and mechanosensitive pathways support the development of biomarkers for pain phenotyping and patient stratification. These insights have direct implications for clinical trial design and interpretation, particularly in addressing discordance between structural and symptomatic outcomes.