Transcriptome and alternative splicing analyses uncover immune-centric pathogenesis in periodontitis versus barrier-dysfunction-driven pathogenesis in peri-implantitis.

Abstract

BACKGROUND: Peri-implantitis (PI) exhibits worse symptoms and prognosis than periodontitis (PD), yet their molecular differences remain unclear. This study aimed to identify these distinctions to clarify their unique pathogeneses. METHODS: Rat models of PD and PI were established via silk-ligation and bacterial inoculation, with healthy rats as controls (CON). Successful model induction was confirmed by three-dimensional micro-CT reconstruction and HE staining. Gingival tissues were collected for transcriptome sequencing to identify differentially expressed genes (DEGs) and alternative splicing (AS) events. Key candidates were validated by RT-qPCR. RESULT: Micro-CT and HE staining revealed significant alveolar bone resorption in both PD and PI groups, with PD exhibiting more severe bone loss . Transcriptomic analysis showed distinct molecular profiles: 2776 DEGs in PD vs CON (1274 up, 1502 down), and 1049 DEGs in PI vs CON (429 up, 620 down). PI vs PD revealed 3193 DEGs (1524 up, 1669 down). Functional enrichment indicated that PD-related DEGs were primarily associated with immune response and inflammatory signaling pathways, whereas PI-related DEGs were enriched in keratinization and epithelial barrier function. AS analysis identified differentially regulated splicing events in both groups, with relevant genes clustered in DNA damage response pathways. RT-qPCR confirmed downregulation of DBP, PACRG and SPAG17, and upregulation of PKP1, GJA1 and LAD1 in PI. Concurrently, the frequencies of AS variants SPAG9 (exon skipping), MYO9B (mutually exclusive exon), and NFRKB (A3SS) were significantly elevated in the PI group. CONCLUSION: PD pathogenesis is characterized by an "inflammation-bone resorption" axis, while PI is defined by "epithelial barrier dysfunction-bone resorption." These findings identify key molecular mechanisms and provide insights for developing targeted therapies.