Modulation of Phosphate/Pyrophosphate Metabolism to Regenerate the Periodontium: A Novel In Vivo Approach

Abstract

Background The developing periodontium is sensitive to local levels of phosphate (Pi) and pyrophosphate (PPi), as demonstrated by cementum phenotypes resulting from loss of function of protein regulators of Pi/PPi homeostasis. The progressive ankylosis protein (ANK) regulates transport of PPi, and Ank knock-out (KO) mice feature rapidly forming and thick cementum. We hypothesized that, besides affecting cementum formation, decreased extracellular PPi levels in Ank KO mice would also impact cementum regeneration. Methods Periodontal fenestration defects (2mm/1mm/0.5mm) were created on the buccal aspects of mandibular molars in Ank KO and wild-type (WT) mice. Mandibles were harvested at 15 and 30 days post-surgery for histology, histomorphometry, evaluation of in vivo fluorochrome labeling, and immunohistochemistry(IHC) for proteins including bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein 1 (DMP1), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). Results A greater amount of new cementum was observed for Ank KO mice at 15 and 30 days post-surgery (p<0.05), that was confirmed by fluorochrome labeling showing a higher new cementum appositional activity in the defect areas in Ank KO vs. controls. At days 15 and 30 during healing, regenerating cementum and associated cells in Ank KO recapitulated expression patterns mapped during development, including limited BSP and positive OPN and DMP1 in the cementum matrix, as well as elevated NPP1 in cementoblasts. Conclusions Within the limits of the study, these findings suggest that reduced local levels of PPi can promote increased cementum regeneration. Therefore, local modulation of Pi/PPi may be a potential therapeutic approach for achieving improved cementum regeneration.

Correction of Hypophosphatasia‐Associated Mineralization Deficiencies In Vitro by Phosphate/Pyrophosphate Modulation in Periodontal Ligament Cells

“…47 The results from these regeneration studies support our findings here. Specifically, we demonstrated that cementum regeneration in Ank KO mice (which feature PP i deficiency) was more rapid and more extensive when compared to comparably treated control mice.…”

Dental and periodontal phenotype in sclerostin knockout mice

“…37 Recently, signalling cascades connecting dentin matrix protein 1 and dentin sialophosphoprotein were studied in rodent models. 35 Similar models with sclerostin might confirm the recent findings, as Wnt/β-catenin signalling is complex. 2 Moreover, mouse models revealing the role of DKK-1, another antagonist of Wnt/β-catenin signalling, on the tooth, the dimension of the tooth and the periodontium would be worth investigating, particularly because DKK1 is a negative regulator of normal bone homeostasis in vivo .…”

“…22 This supports the role of Wnt/β-catenin signalling in the formation of the dentoalveolar complex. 31 Whether sclerostin is functionally linked with the control of acellular cementum in phosphate metabolism 32,33 and mutations of the progressive ankylosis protein and plasma cell membrane glycoprotein-1 genes 34,35 remains unclear. However, mouse models provide valuable insights into the biology of the mysterious process of cementogenesis.…”

Zinc Induces Apatite and Scholzite Formation during Dentin Remineralization

“…Inorganic pyrophosphate (PPi) is present in mineralized tissues and is a potent inhibitor of HAp crystal growth. Increases in Pi concentration will facilitate HAp formation, which is highly sensitive to the balance of Pi/PPi [Cheng and Pritzker, 1983;Rodrigues et al, 2011].…”

“…As a result, Zn 2+ can compete with Ca 2+ for binding to pyrophosphate, even at a very low concentration, resulting in the enhanced formation of HAp [Vasant and Joshi, 2011]. Moreover, the non-specific-tissue alkaline phosphatase that is present in dentin [Rodrigues et al, 2011] and is specifically activated by zinc [Seo et al, 2010;Yamaguchi, 2010] can also hydrolyze pyrophosphates. These two factors probably work in concert to control local levels of pyrophosphates favoring dentin remineralization.…”