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Insights into dental mineralization from three heritable mineralization disorders.

ABSTRACT: Teeth are comprised of three unique mineralized tissues, enamel, dentin, and cementum, that are susceptible to developmental defects similar to those affecting bone. X-linked hypophosphatemia (XLH), caused by PHEX mutations, leads to increased fibroblast growth factor 23 (FGF23)-driven hypophosphatemia and local extracellular matrix disturbances. Hypophosphatasia (HPP), caused by ALPL mutations, results in increased levels of inorganic pyrophosphate (PP_i), a mineralization inhibitor. Generalized arterial calcification in infancy (GACI), caused by ENPP1 mutations, results in vascular calcification due to decreased PP_i, later compounded by FGF23-driven hypophosphatemia. In this perspective, we compare and contrast dental defects in primary teeth associated with XLH, HPP, and GACI, briefly reviewing genetic and biochemical features of these disorders and findings of clinical and preclinical studies to date, including some of our own recent observations. The distinct dental defects associated with the three heritable mineralization disorders reflect unique processes of the respective dental hard tissues, revealing insights into their development and clues about pathological mechanisms underlying such disorders.

SUBMITTER: Chavez MB

PROVIDER: S-EPMC7530110 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Insights into dental mineralization from three heritable mineralization disorders.

Chavez Michael B MB Kramer Kaitrin K Chu Emily Y EY Thumbigere-Math Vivek V Foster Brian L BL

Journal of structural biology 20200803 1

Teeth are comprised of three unique mineralized tissues, enamel, dentin, and cementum, that are susceptible to developmental defects similar to those affecting bone. X-linked hypophosphatemia (XLH), caused by PHEX mutations, leads to increased fibroblast growth factor 23 (FGF23)-driven hypophosphatemia and local extracellular matrix disturbances. Hypophosphatasia (HPP), caused by ALPL mutations, results in increased levels of inorganic pyrophosphate (PP<sub>i</sub>), a mineralization inhibitor. ...[more]

PMID: 32758526

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Project description:The importance of phosphate (Pi) as an essential component of hydroxyapatite crystals suggests a key role for membrane proteins controlling Pi uptake during mineralization in the tooth. To clarify the involvement of the currently known Pi transporters (Slc17a1, Slc34a1, Slc34a2, Slc34a3, Slc20a1, Slc20a2, and Xpr1) during tooth development and mineralization, we determined their spatiotemporal expression in murine tooth germs from embryonic day 14.5 to postnatal day 15 and in human dental samples from Nolla stages 6 to 9. Using real-time polymerase chain reaction, in situ hybridization, immunohistochemistry, and X-gal staining, we showed that the expression of Slc17a1, Slc34a1, and Slc34a3 in tooth germs from C57BL/6 mice were very low. In contrast, Slc34a2, Slc20a1, Slc20a2, and Xpr1 were highly expressed, mostly during the postnatal stages. The expression of Slc20a2 was 2- to 10-fold higher than the other transporters. Comparable results were obtained in human tooth germs. In mice, Slc34a2 and Slc20a1 were predominantly expressed in ameloblasts but not odontoblasts, while Slc20a2 was detected neither in ameloblasts nor in odontoblasts. Rather, Slc20a2 was highly expressed in the stratum intermedium and the subodontoblastic cell layer. Although Slc20a2 knockout mice did not show enamel defects, mutant mice showed a disrupted dentin mineralization, displaying unmerged calcospherites at the mineralization front. This latter phenotypical finding raises the possibility that Slc20a2 may play an indirect role in regulating the extracellular Pi availability for mineralizing cells rather than a direct role in mediating Pi transport through mineralizing plasma cell membranes. By documenting the spatiotemporal expression of Pi transporters in the tooth, our data support the possibility that the currently known Pi transporters may be dispensable for the initiation of dental mineralization and may rather be involved later during the tooth mineralization scheme.

Project description:The addition of charged polymers, like poly-aspartic acid (pAsp), to mineralizing solutions allows for transport of calcium and phosphate ions into the lumen of collagen fibrils and subsequent crystallization of oriented apatite crystals by the so-called Polymer-Induced Liquid Precursor (PILP) mineralization process, leading to the functional recovery of artificial dentin lesions by intrafibrillar mineralization of collagen. OBJECTIVE:To evaluate the feasibility of applying the PILP method as part of a restorative treatment and test for effectiveness to functionally remineralize artificial lesions in dentin. MATERIALS AND METHODS:Two methods of providing pAsp to standardized artificial lesions during a restorative procedure were applied: (A) pAsp was mixed into commercial RMGI (resin modified glass ionomer) cement formulations and (B) pAsp was added at high concentration (25mg/ml) in solution to rehydrate lesions before restoring with a RMGI cement. All specimens were immersed in simulated body fluid for two weeks to allow for remineralization and then analyzed for dehydration shrinkage, integrity of cement-dentin interface, degree of mineralization, and changes in the nanomechanical profile (E-modulus) across the lesion. RESULTS:After the remineralization treatment, lesion shrinkage was significantly reduced for all treatment groups compared to demineralized samples. Pores developed in RMGI when pAsp was added. A thin layer at the dentin-cement interface, rich in polymer formed possibly from a reaction between pAsp and the RMGI. When analyzed by SEM under vacuum, most lesions delaminated from the cement interface. EDS-analysis showed some but not full recovery of calcium and phosphorous levels for treatment groups that involved pAsp. Nanoindentations placed across the interface indicated improvement for RMGI containing 40% pAsp, and were significantly elevated when lesions were rehydrated with pAsp before being restored with RMGI. In particular the most demineralized outer zone recovered substantially in the elastic modulus, suggesting that functional remineralization has been initiated by pAsp delivery upon rehydration of air-dried demineralized dentin. In contrast, the effectiveness of the RMGI on functional remineralization of dentin was minimal when pAsp was absent. SIGNIFICANCE:Incorporation of pAsp into restorative treatments using RMGIs promises to be a feasible way to induce the PILP-mineralization process in a clinical setting and to repair the structure and properties of dentin damaged by the caries process.

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Insights into dental mineralization from three heritable mineralization disorders.

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Insights into dental mineralization from three heritable mineralization disorders.

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