From mechanical adaptation to innate immune reprogramming in osteoarthritis: a load-immunity framework

Osteoarthritis (OA) is a complex joint disease characterized by the interplay between mechanical exposure and low-grade sterile inflammation. However, the coexistence of these two factors does not fully explain why a normally adaptive response becomes self-sustaining. This review focuses on understanding how specific loading conditions influence joint-resident cells to transition from reversible mechanoadaptation to persistent innate immune dysregulation. The term innate immune reprogramming refers to a load-induced change in the activation threshold, metabolic state, secretory output, or intercellular behavior of a resident or recruited cell that outlasts the initiating mechanical episode or changes its response to subsequent loading. The evidence is organized into three levels: initiating mechanical events, intracellular amplification through calcium overload, mitochondrial stress, NLRP3, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, and tissue-specific consequences propagated through interactions among chondrocytes, macrophages, fibroblast-like synoviocytes (FLS), subchondral bone cells, and sensory neurons. The roles of Piezo1, TRPV4, NLRP3, and cGAS-STING are context-dependent and not uniformly pathogenic switches. The review also distinguishes between causal preclinical experiments, human association studies, and proposed joint-level networks. Recent studies have shown that mitochondria-derived extracellular vesicles released by infrapatellar fat pad mesenchymal stromal cells can transfer mitochondrial DNA (mtDNA) to chondrocytes, illustrating the potential for mitochondrial danger signals to propagate extracellularly. However, the quantitative importance of this mechanism in human OA remains unresolved. In terms of translation, load correction has the strongest immediate rationale, while molecular interventions require tissue-specific delivery, disease-stage selection, pharmacodynamic biomarkers, and preservation of physiological mechanoadaptation.