RANKL-RANK signaling promotes cigarette smoke-induced emphysema with MMP-9 upregulation in alveolar macrophages.

Background: Chronic obstructive pulmonary disease (COPD) is a leading global health problem, with pulmonary emphysema as one of its hallmark pathological features. Matrix metalloproteinase-9 (MMP-9), predominantly derived from alveolar macrophages, has been implicated in extracellular matrix degradation. However, the upstream regulatory signals responsible for MMP-9 induction in cigarette smoke (CS)-related COPD remain incompletely understood. We investigated whether receptor activator of nuclear factor-κB ligand (RANKL) and its receptor RANK are involved in this process. Methods: We localized RANKL and RANK in lung tissues of mice subjected to long-term CS exposure. Emphysema was evaluated in CS-exposed mice that received intraperitoneal injections of either an anti-mouse RANKL monoclonal antibody or a rat IgG2a kappa isotype control antibody. Next, we examined their expression under cigarette smoke extract (CSE) stimulation in the MH-S mouse alveolar macrophage cell line. Finally, we evaluated the functional role of RANKL in regulating CS-induced MMP-9 production using neutralizing antibodies. Results: Conclusion: RANKL-RANK signaling is associated with increased MMP-9 expression in alveolar macrophages and contributes to CS-induced emphysema. Targeting this pathway attenuates structural damage and functional impairment and may represent a potential therapeutic strategy in COPD-related emphysema.