Damage-Associated Molecular Patterns and Trained Immunity of Monocyte–Macrophage Populations in Osteoarthritis: Potential Molecular Links and Therapeutic Opportunities

Abstract

Highlights What are the main findings? Direct human evidence supports an HMGB1-associated trained phenotype in circulating monocytes from knee OA, although broader OA-specific validation remains limited. DAMP sensing may converge with epigenetic and immunometabolic reprogramming to sustain altered monocyte–macrophage responsiveness in OA. What are the implications of the main findings? Evidence stratification is essential for distinguishing demonstrated OA-specific relationships from mechanisms extrapolated from other inflammatory conditions. The interface between DAMP signaling and trained immunity provides testable targets, but causal and phenotype-specific validation is required before clinical translation. Abstract Osteoarthritis (OA) is now widely discussed as a whole-joint immunometabolic disease involving cartilage, synovium, and subchondral bone, rather than as cartilage degeneration driven only by mechanical stress. Tissue injury, cell death, mitochondrial dysfunction, and extracellular matrix degradation can lead to the persistent release of damage-associated molecular patterns (DAMPs), which activate innate immune responses through pattern recognition receptors (PRRs). A key unresolved issue is why inflammation can persist or recur when there is no continuous external stimulus. Trained immunity provides an emerging framework for approaching this problem, with initial direct evidence now available in circulating monocytes from knee OA but broader validation still lacking. Following an initial stimulus and a subsequent resting interval, monocytes and macrophages may retain epigenetic and metabolic alterations that modify their responses to later homologous or heterologous challenges. This review summarizes the sources of DAMPs and their recognition mechanisms in the OA microenvironment, with particular attention to their potential links with trained immunity in monocyte–macrophage populations. We discuss PRR-mediated changes in chromatin accessibility, histone modifications, DNA methylation, and non-coding RNA regulation, as well as immunometabolic events such as enhanced glycolysis, tricarboxylic acid cycle remodeling, mitochondrial dysfunction, and accumulation of key metabolites. We also examine how monocyte–macrophage populations with persistent hyperresponsiveness after stimulus withdrawal and restimulation may contribute to persistent synovitis, cartilage matrix degradation, and abnormal subchondral bone remodeling. Finally, we summarize therapeutic opportunities potentially relevant to the proposed links between DAMP signaling and trained immunity. Recent evidence that high-mobility group box 1 (HMGB1) primes a trained phenotype in circulating monocytes provides initial direct support for DAMP-associated trained immunity in knee OA. However, its generalizability across independent cohorts, other DAMP classes, myeloid-cell compartments, disease stages, and OA phenotypes remains to be established.