Periodontitis is an inflammatory disease caused by pathogenic oral microorganisms that induce the destruction of periodontal tissue. We sought to identify the relevant differentially expressed genes (DEGs) and clarify the mechanism underlying the rapid alveolar bone loss by using ligature-induced periodontitis in mice. A silk ligature was tied around the maxillary left second molar in 9-week-old C57BL/6 J male mice. In-vivo micro-CT analysis revealed that ligation induced severe bone loss. RNA-sequencing analysis, to examine host responses at 3 days post-ligation, detected 12,853 genes with fragments per kilobase of exon per million mapped reads ≥ 1, and 78 DEGs. Gene ontology term enrichment analysis revealed the expression profiles related to neutrophil chemotaxis and inflammatory responses were significantly enriched in the ligated gingiva. The expression levels of innate immune response-related genes, including S100a8 and S100a9, were significantly higher in the ligated side. S100A8 was strongly detected by immunohistochemistry at the attached epithelium in ligated sites. Inhibition of S100A8 and S100A9 expression revealed that they regulated IL1B and CTSK expression in Ca9-22 cells. Thus, innate immune response-related molecules might be associated with the burst-destruction of periodontal tissue in ligature-induced periodontitis. Especially, S100A8 and S100A9 may play an important role in alveolar bone resorption.