Inactivation of Sufu in cementoblasts accelerates external tooth root resorption

Cementum has been empirically regarded as an antiresorptive barrier against tooth roots. However, little is known about the factors of homeostasis and resistant mechanisms of tooth roots against resorption. Here, we investigated cementum factors and their interaction against resorption using transgenic mice exhibiting external cervical root resorption (ECRR). Ectopically thickened cervical cementum caused by functional inactivation of ectonucleotide pyrophosphotase/phosphodiesterase 1 (Enpp1) was susceptible to ECRR with aging. In addition, the inactivation of the suppressor of fused (Sufu), a Hedgehog signaling inhibitor, in cementoblasts led to ECRR. Interestingly, concurrent inactivation of Sufu and Enpp1 in cementoblasts remarkably exacerbated ECRR with higher Rankl expression. Cellular and molecular analyses using cementoblasts and bone marrow-derived macrophages indicated that Dickkopf-related protein 1 (Dkk1) induced by the inactivation of Sufu in cementoblasts has roles in the acceleration of ECRR triggered by Enpp1 inactivation. Using compound mutant mice for concurrent Wntless and Enpp1 inactivation, this synergistic cooperation of Dkk1 and Npp1 for resorption found in double mutant Sufu and Enpp1 mice was confirmed by the reproduction of amplified ECRR. On the basis of these findings, we conclude that proper Npp1 function and sustained Wnt activity in the cervical cementum are essential for the homeostasis of tooth roots against resorption in a physiological state.