Regulatory Effects of Pyrophosphate Metabolism on Cementogenesis

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Abstract

Cementum that envelops the tooth root provides an interface between the tooth proper and the supporting periodontal tissues. Evidence suggests cementum is uniquely sensitive to modulation of inorganic phosphate (Pᵢ), a component of hydroxyapatite, and pyrophosphate (PPᵢ), an inhibitor of hydroxyapatite precipitation. Modulation of PPᵢ concentration at sites of bone and tooth mineralization is important in guiding proper hard tissue formation. Factors increasing PPj include progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1), while tissue nonspecific alkaline phosphatase (TNAP) reduces PPᵢ by hydrolysis. To elucidate mechanisms by which root development is shaped by Pᵢ/PPᵢ homeostasis, studies were designed employing in vivo and in vitro approaches. In mice where the gene for TNAP (Akp2) was ablated, increased PP, caused aplasia or severe hypoplasia of the acellular extrinsic fiber cementum (AEFC). Expression of a key cementoblast gene bone sialoprotein (Bsp) was unaltered, suggesting the mechanism was physical-chemical inhibition of HAP rather than directed effects on cementoblasts. Conversely, in both Ank and Enppl KO mice, AEFC increased more than 10-fold versus controls, while other dentoalveolar tissues, including cellular intrinsic fiber cementum (CIFC), were unaltered. In both Ank and Enpp1 KO, AEFC featured a cellular cementum-like phenotype of dispersed BSP, and increased osteopontin (OPN) and dentin matrix protein 1 (DMP1) expression. Notably, Ank KO triggered markedly increased cementoblast NPP1 expression, suggesting attempted compensation for PP: dysregulation. In vitro studies provided a mechanistic platform for probing the association of Ank, Enppl, Opn, and Dmp1 with cementoblast mineralization. Under mineralizing conditions, OCCM.30 cementoblasts exhibited an increase in Ank and Enpp1, as well as Opn and Dmp1, and induction coincided with mineral nodule formation, suggesting these genes are functionally coupled to cementoblast mineralization. While low PPᵢ presided over robust mineralization and induction of PPr and mineral-associated genes, establishment of high PPᵢ conditions was sufficient to inhibit both mineralization and associated gene induction. Thus, PPᵢ is capable of governing both mineral apposition and cementoblast gene expression, and PPᵢ regulation is revealed as a major determinant defining acellular cementum formation. These results underscore the concept that PPᵢ modulation has potential as a novel approach to promote cementum regeneration.

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