Time-Series Transcriptomics Identifies Xanthine Dehydrogenase in Injured Neurons Correlated With Orthodontic Pain.

Abstract

BACKGROUND: Orthodontic tooth movement (OTM) pain poses a significant clinical challenge, yet its underlying molecular and cellular mechanisms remain incompletely understood. METHODS: We established a mouse OTM model validated by micro-CT and histology, alongside pain assessments (Mouse Grimace Scale, bite force). Bulk RNA-seq was performed on trigeminal ganglion (TG) tissues, integrated with public single-cell RNA-seq data for a more comprehensive view, and key genes were confirmed via qPCR and immunofluorescence. A user-friendly web platform (OTMPTGTA) was developed to enable researchers to explore differentially expressed genes, gene correlations and gene-set analyses without specialised coding skills. RESULTS: OTM induced both significant tooth movement and heightened pain, peaking at Day 3. Transcriptomic analyses pinpointed an Atf3+ population of injured TG neurons that showed marked upregulation of xanthine dehydrogenase (Xdh) during peak pain; by Day 14, both gene expression levels and pain scores subsided. QPCR and immunofluorescence confirmed coexpression of Atf3 and Xdh at Day 3, implicating Xdh in nociceptive signalling. The OTMPTGTA platform facilitates further exploration of these and other potential pain-related pathways, offering novel insights for targeted intervention. CONCLUSIONS: Xdh is highly expressed in Atf3+ injured neurons during OTM pain, likely intensifying nociceptive signals through oxidative and inflammatory pathways. These findings highlight Xdh as a promising therapeutic target for alleviating orthodontic pain while preserving effective tooth movement.