Biomarkers for Treatment Response in Orthodontics: Molecular Mechanisms, Clinical Utility, and Future Directions.

Orthodontic tooth movement (OTM) is a biologically driven process resulting from the mechanically induced remodeling of the periodontal ligament (PDL) and alveolar bone. A marked inter-individual variability exists in the rate of tooth movement, susceptibility to adverse outcomes such as external apical root resorption (EARR), and overall treatment response. This narrative review synthesizes current evidence on molecular, genetic, and epigenetic biomarkers that underline these differences. We summarize established local biomarkers derived from gingival crevicular fluid and saliva, including inflammatory cytokines, matrix metalloproteinases, and bone remodeling mediators reflecting OTM compression- and tension-side biology. Beyond fluid biomarkers, growing attention is given to genetic and epigenetic determinants of OTM. Specific gene mutations are associated with impaired or absent tooth movement, while multiple single-nucleotide polymorphisms have been linked to increased risk of EARR. Recent studies further demonstrate that orthodontic forces induce epigenetic remodeling in PDL cells, including DNA methylation changes in the gene promoters, histone modifications, and force-responsive non-coding RNAs such as miR-21 and miR-146a, which collectively regulate osteoclastogenesis, inflammation, and tissue adaptation. These findings indicate that OTM is governed by an integrated network combining mechanical stimuli with genetic predisposition and dynamic epigenetic regulation. Understanding these mechanisms provides a foundation for the development of biomarker-guided, patient-specific therapeutic strategies.