Neutrophils interact with osteogenic cells through cytokine production to promote bone destruction in periodontitis. In periodontitis, immune cells accumulate in the oral mucosa and induce RANKL expression in osteogenic cells, leading to bone loss. Single-cell RNA sequencing of mouse periodontal lesions revealed that neutrophils interact with osteogenic cells through cytokine production, with oncostatin M (OSM) being a key mediator. OSM induces RANKL expression in osteogenic cells, and its deletion in osteogenic cells ameliorates periodontitis-induced bone loss. Epigenomic analysis identified an OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed reduced periodontal bone loss while maintaining physiological bone metabolism. These findings highlight the role of neutrophils in bone regulation during bacterial infection and provide a novel mechanism of osteoimmune crosstalk. The study also demonstrates that the neutrophil-osteogenic cell interaction is critical for periodontitis-induced bone destruction, emphasizing the importance of understanding immune-stromal cell interactions in disease pathogenesis. The results suggest that targeting the OSM/RANKL axis could be a potential therapeutic strategy for periodontitis and related diseases.Neutrophils interact with osteogenic cells through cytokine production to promote bone destruction in periodontitis. In periodontitis, immune cells accumulate in the oral mucosa and induce RANKL expression in osteogenic cells, leading to bone loss. Single-cell RNA sequencing of mouse periodontal lesions revealed that neutrophils interact with osteogenic cells through cytokine production, with oncostatin M (OSM) being a key mediator. OSM induces RANKL expression in osteogenic cells, and its deletion in osteogenic cells ameliorates periodontitis-induced bone loss. Epigenomic analysis identified an OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed reduced periodontal bone loss while maintaining physiological bone metabolism. These findings highlight the role of neutrophils in bone regulation during bacterial infection and provide a novel mechanism of osteoimmune crosstalk. The study also demonstrates that the neutrophil-osteogenic cell interaction is critical for periodontitis-induced bone destruction, emphasizing the importance of understanding immune-stromal cell interactions in disease pathogenesis. The results suggest that targeting the OSM/RANKL axis could be a potential therapeutic strategy for periodontitis and related diseases.