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Runt-related transcription factor 2  (Runx2 )-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 ( Usag-1 )-deficient mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of  Usag-1  expression can enable the recovery of tooth formation in  Runx2 -deficient mice. Here, we tested whether inhibiting the topical expression of  Usag-1  can reverse arrested tooth formation after  Runx2  abrogation. The results showed that local application of  Usag-1  Stealth small interfering RNA (siRNA) promoted tooth development following  Runx2  siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and  Runx2 -knockout (KO) mouse mandibles, treated with  Usag-1  siRNA, revealing that hindered tooth formation was rescued by  Usag-1  knockdown. Furthermore, topically applied  Usag-1  siRNA partially rescued arrested tooth development in  Runx2 -KO mice, demonstrating its potential for regenerating teeth in  Runx2 -deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.

Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice