BackgroundChronic 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.MethodsWe 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.ResultsIn vivo, chronic CS exposure resulted in alveolar enlargement, structural destruction, and decline in lung function, accompanied by increased expression of RANKL, RANK, and MMP-9 in lung tissue. These molecules were predominantly localized to alveolar macrophages. Neutralization of RANKL was associated with reduced MMP-9 expression, attenuated alveolar damage, and improved pulmonary function. In vitro, CSE stimulation of MH-S cells upregulated RANKL and RANK and induced MMP-9 expression, while RANKL blockade partially inhibited this effect.ConclusionRANKL–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.