Abstract
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.
Highlights
Runt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans
To evaluate the effect of uterine sensitization-associated gene-1 (Usag-1) knockdown on tooth development, we investigated mandible explant cultures using serum-free medium containing Stealth small interfering RNA (siRNA)
To investigate whether administration of Usag-1 Stealth siRNAs could rescue the phenotype of inhibited tooth formation caused by Runx[2] knockdown, we co-administered Usag-1 and Runx[2] siRNA, revealing that Usag-1 #304 recovered tooth formation in the presence of Runx[2] Stealth siRNA (P = 0.020), whereas Usag-1 #903 administration resulted in a similar incidence of no tooth formation as observed with Runx[2] knockdown alone (P = 0.656) (Fig. 3). These results demonstrated that hindered tooth formation induced by Runx[2] knockdown was rescued by Usag-1 siRNA #304 treatment in renal capsules transplanted with wild-type mouse mandibles
Summary
Runt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans. 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; it remains unclear whether topical inhibition of Usag-1 expression can enable the recovery of tooth formation in Runx2-deficient mice. A recent study of runt-related transcription factor 2 (Runx2)−/− mice showed that they exhibited arrested tooth development, and this phenotype was compared with that of a patient harboring a unique Arg131Cys missense Runx[2] mutation who exhibited congenitally missing tooth without supernumerary teeth[5]. A genetic link between Usag-1 and Runx[2] has been clearly shown, it remains unclear whether topical inhibition of Usag-1 expression can recover tooth formation in Runx2−/− mice
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