DMXAA accelerates orthodontic tooth movement via macrophage-mediated Rab13-enriched extracellular vesicle release and chemokine secretion

BACKGROUND: Orthodontic tooth movement (OTM) is a complex process involving periodontal tissue remodeling, and safe strategies to accelerate OTM remain a research focus. DMXAA (Vadimezan), a non-toxic immune-modulating drug with established clinical trial data, stimulates the secretion of pro-inflammatory cytokines potentially relevant to OTM, which involves immune-mediated bone remodeling. METHODOLOGY: A murine OTM model was established in C57BL/6 mice, receiving local subperiosteal injections of DMXAA. Tooth movement distance, bone volume fraction, and osteoclast parameters were quantified via Micro-CT and histology. The mechanism was dissected using RNA-sequencing of bone marrow-derived macrophages (BMDMs), sEV proteomics, and functional osteoclastogenesis assays. Macrophage depletion and Rab13 knockdown models were employed to verify specificity. RESULTS: Local DMXAA administration significantly enhance orthodontic tooth movement and rate in mice under orthodontic force application, accompanied by reduced alveolar bone volume and increased osteoclast numbers on the compressive force side. DMXAA induced macrophage accumulation at the force-applied site, polarizing them toward M1-like pro-inflammatory phenotypes characterized by high secretion of CCL5 and CXCL10. Furthermore, small extracellular vesicles derived from DMXAA-treated macrophages, which were enriched with Rab13 protein, contributed to osteoclast fusion and maturation, thereby accelerating OTM. CONCLUSIONS: DMXAA accelerates OTM through a dual mechanism: chemokine-driven osteoclast differentiation and sEV-Rab13-mediated osteoclast fusion. These findings highlight the Rab13-sEV axis as a novel therapeutic target for modulating the periodontal microenvironment and enhancing orthodontic efficiency. Our results elucidated a novel mechanism by which DMXAA accelerated orthodontic tooth movement and suggested it as a potential therapeutic agent to optimize orthodontic treatment.