Trained immunity in bone and joint diseases: context-dependent protection, maladaptive reprogramming, and therapeutic modulation

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Bone and joint diseases are characterized by dysregulated inflammation, bone destruction, and impaired tissue repair. Trained immunity is a form of innate immune memory in which innate immune cells or their progenitors acquire a persistent, functionally altered response to a secondary challenge after priming and a resting interval, supported by metabolic and epigenetic reprogramming. Its consequences vary according to the cellular compartment, tissue microenvironment, and nature of the secondary challenge. To summarize the mechanisms and context-dependent roles of trained immunity in bone and joint diseases and to evaluate emerging bioengineering strategies for its therapeutic modulation. PubMed and Web of Science were searched for publications. Search terms combined “trained immunity” with terms related to osteomyelitis, bone infection, implant-associated infection, prosthetic joint infection, periodontitis, arthritis, osteoclastogenesis, bone loss, macrophages, biomaterials, nanomedicine, and immunoengineering. After screening according to predefined eligibility criteria, 137 publications were included in the narrative synthesis. In infection-related conditions, including osteomyelitis and implant-associated infection, preclinical evidence suggests that controlled local induction of trained immunity may enhance myeloid antimicrobial activity, reduce bacterial burden, improve the control of biofilm-associated infection, and increase resistance to subsequent infection. Conversely, in periodontitis and inflammatory arthritis, maladaptive trained immunity may amplify inflammatory cytokine production, bias myeloid progenitors toward osteoclastogenesis, and aggravate inflammatory bone loss. Hydrogels, nanocarriers, engineered extracellular vesicles, and metabolic–epigenetic modulators may enable spatially and temporally controlled induction or reversal of trained-immunity programs. Trained immunity is a context-dependent regulator of host defense, inflammation, and bone remodeling. Current evidence remains predominantly preclinical. Clinical translation will require standardized evidence criteria, validated biomarkers, clinically representative models, controlled and reversible immune modulation, reproducible efficacy, and long-term safety.