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Abstract Background Skeletal tuberculosis (TB) remains a persistent clinical and research challenge due to its chronic course, osteolytic destruction, and the limitations of existing animal models, which often require high‐level biosafety containment or fail to replicate human skeletal pathology. Methods This study developed a biosafe, accessible, and versatile murine model of skeletal TB using Mycobacterium smegmatis , a fast‐growing, nonpathogenic mycobacterial species with high genomic homology to Mycobacterium tuberculosis. Three infection routes—subperiosteal calvarial injection, intratibial injection, and intracardiac inoculation—were systematically evaluated for their ability to induce localized versus disseminated bone infection under standard biosafety level (BSL)‐1 conditions. Results Subperiosteal calvarial and intratibial injection of M. smegmatis induced localized bone lesions characterized by osteolysis, sequestrum formation, granulomatous inflammation, and increased osteoclast activity. Intratibial infection additionally triggered compartment‐specific immune responses, including neutrophil and macrophage expansion, transient B‐cell depletion, and activation of interferon‐γ + (IFN‐γ + ) T cells, reflecting active immune remodeling at the infection site. Systemic dissemination via intracardiac injection reproducibly generated progressive vertebral and tibial bone destruction with organized granuloma formation and immune cell infiltration but without prominent sequestrum formation. Compared to intratibial infection, intracardiac delivery exhibited lower intragroup variability and more closely recapitulated the diffuse progression of extrapulmonary skeletal tuberculosis. Conclusions This M. smegmatis –based murine model provides a straightforward, reliable, and immunopathologically relevant platform for exploring host–pathogen dynamics, immune‐driven bone destruction, and early‐stage therapeutic testing in skeletal TB, all within standard BSL‐1 laboratories. This model fills a critical gap by enabling BSL‐1 research into skeletal TB mechanisms and drug development.
Jia et al. (Thu,) studied this question.