Npp1 prevents external tooth root resorption by regulation of cervical cementum integrity

Tooth roots embedded in the alveolar bone do not typically undergo resorption while the bone continues remodeling in its physiological state. In this study, we analyzed genetically modified mice with the functional inactivation of nucleotide pyrophosphatase 1 (Npp1), encoded by ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1). This mutation leads to the formation of ectopic cervical cementum vulnerable to external tooth root resorption. Cementoblasts with the inactivation of Enpp1 extensively expressed non-collagenous matrix proteins enriched with bone sialoprotein (Bsp), dentin matrix protein 1 (Dmp1), and osteopontin (Opn), which have roles in mineralization through nucleation and in cell adhesion through the Arg-Gly-Asp (RGD) motif. In cementoblasts with the inactivation of Enpp1, β-catenin was significantly activated and induced the expression of these non-collagenous matrix proteins. In addition, adenosine triphosphate (ATP), which is the most preferred substrate of Npp1, accumulated extracellularly and autocrinally induced the expression of the receptor activator of nuclear factor κB ligand (Rankl) in cementoblasts with inactivated Npp1. Consequently, these results strongly suggest that functional Npp1 preserves cervical cementum integrity and supports the anti-resorptive properties of tooth roots through ATP homeostasis in the physiological state of cervical cementum.