Ablation of Systemic Phosphate‐Regulating Gene Fibroblast Growth Factor 23 (<i>Fgf23</i>) Compromises the Dentoalveolar Complex

Chu, Emily Y.; Fong, Hanson; Blethen, F. A.; Tompkins, Kevin; Foster, Brian L.; Yeh, Kuang Dah; Nagatomo, Kanako J.; Matsa-Dunn, D.; Sitara, Despina; Lanske, Beate; Rutherford, R. Bruce; Somerman, Martha J.

doi:10.1002/ar.21152

Cited by 28 publications

(20 citation statements)

References 89 publications

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“…14,15 Similarly, a dystrophic pulp calcification, root dilaceration, and a thistle shaped pulp have been reported in the tumoral calcinosis patients who are deficient in FGF23 and have increased phosphate levels. 31,32 This ectopic ossification is linked to an increase in apoptosis of the odontoblasts.…”

Section: Discussionmentioning

confidence: 90%

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Dentin matrix protein 1 and phosphate homeostasis are critical for postnatal pulp, dentin and enamel formation

et al. 2012

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Deletion or mutation of dentin matrix protein 1 (DMP1) leads to hypophosphatemic rickets and defects within the dentin. However, it is largely unknown if this pathological change is a direct role of DMP1 or an indirect role of phosphate (Pi) or both. It has also been previously shown that Klotho-deficient mice, which displayed a high Pi level due to a failure of Pi excretion, causes mild defects in the dentinal structure. This study was to address the distinct roles of DMP1 and Pi homeostasis in cell differentiation, apoptosis and mineralization of dentin and enamel. Our working hypothesis was that a stable Pi homeostasis is critical for postnatal tooth formation, and that DMP1 has an antiapoptotic role in both amelogenesis and dentinogenesis. To test this hypothesis, Dmp1-null (Dmp1−/−), Klotho-deficient (kl/kl), Dmp1/Klotho-double-deficient (Dmp1−/−/kl/kl) and wild-type (WT) mice were killed at the age of 6 weeks. Combinations of X-ray, microcomputed tomography (μCT), scanning electron microscopy (SEM), histology, apoptosis and immunohistochemical methods were used for characterization of dentin, enamel and pulp structures in these mutant mice. Our results showed that Dmp1−/− (a low Pi level) or kl/kl (a high Pi level) mice displayed mild dentin defects such as thin dentin and a reduction of dentin tubules. Neither deficient mouse line exhibited any apparent changes in enamel or pulp structure. However, the double-deficient mice (a high Pi level) displayed severe defects in dentin and enamel structures, including loss of dentinal tubules and enamel prisms, as well as unexpected ectopic ossification within the pulp root canal. TUNEL assay showed a sharp increase in apoptotic cells in ameloblasts and odontoblasts. Based on the above findings, we conclude that DMP1 has a protective role for odontoblasts and ameloblasts in a pro-apoptotic environment (a high Pi level).

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Section: Discussionmentioning

confidence: 90%

“…11,13 Both Fgf23- null and Klotho -deficient mice are reported to have mild dentin malformation and increased apoptosis in odontoblasts, which is due to a high phosphate level. 14,15 …”

Section: Introductionmentioning

confidence: 99%

Dentin matrix protein 1 and phosphate homeostasis are critical for postnatal pulp, dentin and enamel formation

et al. 2012

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“…Immunohistochemistry (IHC) was performed on paraffin sections using an avidin-biotinylated peroxidase enzyme complex (ABC) based kit (Vector Labs, Burlingame, CA) with 3-amino-9-ethylcarbazole (AEC) or 3, 3’-diaminobenzidine (DAB) chromogenic substrates (Vector Labs), as described in more detail previously [22]. Primary antibodies included: Rabbit polyclonal anti-cytokeratin 14 (Covance, Berkeley, CA, USA), rabbit polyclonal anti-Proliferating Cell Nuclear Antigen (PCNA) (Santa Cruz, CA, USA), rabbit polyclonal anti-ß-catenin (H-102, Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), rabbit anti-nuclear factor IC (NFIC; a gift from Dr. J.C. Park, Seoul National University, Korea) [88], rabbit polyclonal anti-dentin sialoprotein (DSP) LF-153 (a gift from Dr. Larry Fisher, NIDCR/NIH, Bethesda, MD, USA)[89], rat anti-tissue nonspecific alkaline phosphatase (TNAP, R&D Systems, Minneapolis, MN, USA)[90], rabbit polyclonal anti-collagen type 1a1 (COL1A1) LF-68 (a gift from Dr. Larry Fisher)[91], rabbit polyclonal anti-collagen type 12 (COLXII) KR-33 (a gift from Dr. Manual Koch, University of Cologne, Germany)[92], rabbit polyclonal anti-bone sialoprotein (BSP; a gift from Dr. Renny Franceschi, University of Michigan, Ann Arbor, MI, USA)[70], polyclonal rabbit anti-osteopontin (OPN) LF-175 (a gift from Dr. Larry Fisher, NIDCR/NIH)[70], and rabbit polyclonal anti-periostin (POSTN; Abcam, Cambridge, MA).…”

Section: Methodsmentioning

confidence: 99%

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

Snider

Wimer

et al. 2016

Matrix Biology

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Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a transmembrane zinc-endopeptidase that breaks down extracellular matrix components, including several collagens, during tissue development and physiological remodeling. MT1-MMP-deficient mice (MT1-MMP−/−) feature severe defects in connective tissues, such as impaired growth, osteopenia, fibrosis, and conspicuous loss of molar tooth eruption and root formation. In order to define the functions of MT1-MMP during root formation and tooth eruption, we analyzed the development of teeth and surrounding tissues in the absence of MT1-MMP. In situ hybridization showed that MT1-MMP was widely expressed in cells associated with teeth and surrounding connective tissues during development. Multiple defects in dentoalveolar tissues were associated with loss of MT1-MMP. Root formation was inhibited by defective structure and function of Hertwig's epithelial root sheath (HERS). However, no defect was found in creation of the eruption pathway, suggesting that tooth eruption was hampered by lack of alveolar bone modeling/remodeling coincident with reduced periodontal ligament (PDL) formation and integration with the alveolar bone. Additionally, we identified a significant defect in dentin formation and mineralization associated with the loss of MT1-MMP. To segregate these multiple defects and trace their cellular origin, conditional ablation of MT1-MMP was performed in epithelia and mesenchyme. Mice featuring selective loss of MT1-MMP activity in the epithelium were indistinguishable from wild type mice, and importantly, featured a normal HERS structure and molar eruption. In contrast, selective knock-out of MT1-MMP in Osterix-expressing mesenchymal cells, including osteoblasts and odontoblasts, recapitulated major defects from the global knock-out including altered HERS structure, short roots, defective dentin formation and mineralization, and reduced alveolar bone formation, although molars were able to erupt. These data indicate that MT1-MMP activity in the dental mesenchyme, and not in epithelial-derived HERS, is essential for proper tooth root formation and eruption. In summary, our studies point to an indispensable role for MT1-MMP-mediated matrix remodeling in tooth eruption through effects on bone formation, soft tissue remodeling and organization of the follicle/PDL region.

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“…IHC was performed as previously described 20,26 . Mouse mandible tissues were deparaffinized in xylene and rehydrated using decreased graded dilutions of ethanol.…”

Section: Methodsmentioning

confidence: 99%

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

Rodrigues

Nagatomo

Foster

et al. 2011

Journal of Periodontology

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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.

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Ablation of Systemic Phosphate‐Regulating Gene Fibroblast Growth Factor 23 (Fgf23) Compromises the Dentoalveolar Complex

Cited by 28 publications

References 89 publications

Dentin matrix protein 1 and phosphate homeostasis are critical for postnatal pulp, dentin and enamel formation

Dentin matrix protein 1 and phosphate homeostasis are critical for postnatal pulp, dentin and enamel formation

Multiple essential MT1-MMP functions in tooth root formation, dentinogenesis, and tooth eruption

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

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