The study investigates the role of neutrophil-osteogenic cell interactions in bone destruction during periodontitis, a prevalent infectious disease. Single-cell RNA sequencing (scRNA-seq) analysis of mouse periodontal lesions revealed that neutrophils significantly accumulate and interact with osteogenic cells through cytokine production. Specifically, oncostatin M (OSM) induced receptor activator of nuclear factor-κB ligand (RANKL) expression in osteoblasts and periodontal ligament cells, which are key sources of RANKL in periodontal bone loss. Deletion of the OSM receptor in osteogenic cells reduced periodontitis-induced bone loss. Epigenomic data identified an OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this region showed decreased periodontal bone loss while maintaining normal bone metabolism. These findings highlight the neutrophil-osteogenic cell axis as a novel mechanism underlying immune-stromal cell interactions in periodontitis, providing insights into the regulation of bone destruction during bacterial infection.The study investigates the role of neutrophil-osteogenic cell interactions in bone destruction during periodontitis, a prevalent infectious disease. Single-cell RNA sequencing (scRNA-seq) analysis of mouse periodontal lesions revealed that neutrophils significantly accumulate and interact with osteogenic cells through cytokine production. Specifically, oncostatin M (OSM) induced receptor activator of nuclear factor-κB ligand (RANKL) expression in osteoblasts and periodontal ligament cells, which are key sources of RANKL in periodontal bone loss. Deletion of the OSM receptor in osteogenic cells reduced periodontitis-induced bone loss. Epigenomic data identified an OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this region showed decreased periodontal bone loss while maintaining normal bone metabolism. These findings highlight the neutrophil-osteogenic cell axis as a novel mechanism underlying immune-stromal cell interactions in periodontitis, providing insights into the regulation of bone destruction during bacterial infection.