S100A7 promotes orthodontic tooth movement by enhancing osteoclastogenesis via the receptor for advanced glycation end products.

Abstract

Introduction: Orthodontic tooth movement (OTM) requires coordinated remodeling of the periodontal ligament (PDL) and alveolar bone, but clinically relevant molecular regulators remain incompletely defined. We investigated damage-associated molecular patterns (DAMPs) in human PDL and the mechanism by which a candidate DAMP regulates OTM.

Methods: PDL from premolars exposed or not exposed to 7 days of orthodontic force underwent tandem mass tag-based proteomics. Candidate expression was validated by enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and immunohistochemistry. Wild-type and mS100a7a15-knockout mouse OTM models, local mS100a7a15 administration, and primary murine osteoclast assays were used to assess function and mechanism.

Results: S100A7 was upregulated in force-loaded human PDL and peaked at day 7; its murine homolog, mS100a7a15, showed a similar pattern and was enriched on the compression side. mS100a7a15 deficiency reduced osteoclastogenesis, alveolar bone resorption, and OTM. Recombinant mS100a7a15 enhanced receptor activator of nuclear factor κB (NF-κB) ligand-induced osteoclast differentiation, ubiquitin-conjugating enzyme E2 N (UBE2N) expression, tumor necrosis factor receptor-associated factor 6 (TRAF6) ubiquitination, and NF-κB activation. Receptor for advanced glycation end products antagonism attenuated NF-κB activation and osteoclastogenesis, whereas Ube2n knockdown reduced TRAF6 ubiquitination and osteoclast differentiation. Local mS100a7a15 administration accelerated OTM without further reducing distal alveolar bone height in the 7-day model.

Conclusions: S100A7 promotes osteoclast-mediated OTM through the receptor for advanced glycation end products, UBE2N, TRAF6, and NF-κB axis. This pathway may provide a target for modulating orthodontic treatment rate, although long-term periodontal and root safety requires evaluation.