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

Osteoarthritis (OA) is a whole-joint disease in which mechanical exposure and low-grade sterile inflammation interact, but their coexistence does not by itself explain why a normally adaptive response becomes self-sustaining. This Mini Review therefore focuses on a narrower question: how do specific loading conditions push joint-resident cells from reversible mechanoadaptation into persistent innate immune dysregulation? We define innate immune reprogramming operationally as 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. We organize the evidence 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. Piezo1, TRPV4, NLRP3, and cGAS-STING are treated as context-dependent nodes rather than uniformly pathogenic switches. We also distinguish causal preclinical experiments from human association studies and from proposed joint-level networks. Recent evidence that mitochondria-derived extracellular vesicles released by infrapatellar fat pad mesenchymal stromal cells can transfer mitochondrial DNA (mtDNA) to chondrocytes illustrates how mitochondrial danger signals may propagate extracellularly, although its quantitative importance in human OA remains unresolved. Translationally, load correction has the strongest immediate rationale, whereas molecular interventions require tissue-specific delivery, disease-stage selection, pharmacodynamic biomarkers, and preservation of physiological mechanoadaptation.