The osteoclast blind spot and other unresolved mechanisms in the exosomal theory of tuberculosis-induced osteoporosis.

The recent study by Zhao et al. ( Inflamm Res. 2025) proposed a novel paradigm in which exosomal miR-125b-5p from Mycobacterium tuberculosis-infected macrophages impairs osteoblast function by targeting IGF2, thereby linking pulmonary infection to systemic osteoporosis. While this work provides a valuable mechanistic insight, our letter offers a critical appraisal to contextualize its findings and highlight pivotal unanswered questions. We posit that the proposed pathway, though compelling, requires further validation to establish direct causality in vivo, independent of the well-established role of systemic inflammatory cytokines. Furthermore, the model remains incomplete as it overlooks the potential synergistic impact of the exosomal cargo on osteoclast activation, thereby presenting only a partial view of the bone remodeling unit. Substantive questions regarding the specificity of miR-125b-5p as the sole effector, the biodistribution mechanisms of these exosomes, and their pathogen-specific nature also warrant urgent investigation. Addressing these gaps is not merely academic but is crucial for assessing the true therapeutic potential of targeting this exosomal axis in clinical practice.