Management of Musculoskeletal Injuries with an Inflammatory Damage-Associated Molecular Pattern (DAMP) Etiology

INTRODUCTION: Musculoskeletal injuries (MSKI) often progress from acute tissue damage to chronic pain and dysfunction when mechanical overload and microdamage sustain sterile inflammation and neuroimmune sensitization. These processes amplify nociception, impair loading tolerance, and limit the efficacy of rehabilitation, underscoring the need for mechanism-based strategies that interrupt the transition from acute injury to chronic musculoskeletal disease. METHODS: This etiological review was conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. A comprehensive search of PubMed/MEDLINE and Google Scholar (1990-2026) identified mechanistic, translational, and therapeutic research reports that examined damage-associated molecular pattern (DAMP) signaling, innate immune activation, stromal cell responses, nociceptor sensitization, and interventions targeting these pathways. Eligible studies addressed DAMP-related mechanisms in musculoskeletal tissues or evaluated therapies that modulate the underlying inflammatory and mechanobiological drivers of chronic MSKI. Information was synthesized thematically to construct an integrated model of how DAMPs contribute to chronicity. RESULTS: Across tendon, cartilage, ligament, muscle, and fibrocartilage, mechanical overload and microdamage trigger the release of DAMPs that activate Toll-like receptors (TLRs), receptor for advanced glycation end-products (RAGE), and inflammasome pathways, thereby sustaining cytokine production, stromal cell activation, and nociceptor sensitization. Persistent DAMP signaling is strongly associated with impaired inflammation resolution, failed tissue healing, and progression to chronic tendinopathy, osteoarthritis, and mechanical low back pain. Emerging therapeutic approaches, including targeted loading, regenerative injections, metabolic modulation, and immune-modifying strategies, demonstrate potential to attenuate DAMP activity, promote resolution, and restore tissue homeostasis. CONCLUSIONS: Sterile inflammation driven by DAMPs provides a unifying mechanistic framework explaining why many musculoskeletal injuries fail to resolve and instead evolve into chronic, refractory conditions. Therapies that modulate DAMP signaling, enhance inflammatory resolution, and normalize mechanobiological loading represent promising avenues for preventing or reversing chronic MSKI pathology. A mechanistically informed approach may improve clinical outcomes by addressing the etiological drivers rather than the downstream symptoms of chronic musculoskeletal disease.