Transforming Growth Factor-Beta Signaling Regulates Tooth Root Dentinogenesis By Cooperation With Wnt Signaling

Proper differentiation of odontoblasts is crucial for the development of tooth roots. Previous studies have reported the osteogenic/odontogenic potential of pre-odontoblasts during root odontoblast differentiation. However, the underlying molecular pathway that orchestrates these processes remains largely unclear. In this study, ablation of transforming growth factor-beta receptor type 2 (Tgfbr2) in root pre-odontoblasts resulted in abnormal formation of root osteodentin, which was associated with ectopic osteogenic differentiation of root odontoblasts. Disrupting TGF-beta signaling caused upregulation of Wnt signaling characterized by increased Wnt6, Wnt10a, Tcf-1, and Axin2 expression. Interestingly, inhibiting Wnt signaling by deleting Wntless (wls) in Osteocalcin (Ocn)-Cre; Tgfbr2(fl/fl); Wls(fl/fl) mice or overexpressing the Wnt antagonist Dkk1 in Ocn-Cre; Tgfbr2(fl/fl); ROSA26(Dkk1) mice decreased ectopic osteogenic differentiation and arrested odontoblast differentiation. Our results suggest that TGF-beta signaling acts with Wnt signaling to regulate root odontogenic differentiation.