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Central role of pyrophosphate in acellular cementum formation.

Foster BL, Nagatomo KJ, Nociti FH, Fong H, Dunn D, Tran AB, Wang W, Narisawa S, Millán JL, Somerman MJ - PLoS ONE (2012)

Bottom Line: Though PP(i) regulators are widely expressed, cementoblasts selectively expressed greater ANK and NPP1 along the root surface, and dramatically increased ANK or NPP1 in models of reduced PP(i) output, in compensatory fashion.In vitro mechanistic studies confirmed that under low PP(i) mineralizing conditions, cementoblasts increased Ank (5-fold) and Enpp1 (20-fold), while increasing PP(i) inhibited mineralization and associated increases in Ank and Enpp1 mRNA.These findings underscore developmental differences in acellular versus cellular cementum, and suggest new approaches for cementum regeneration.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Oral Connective Tissue Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, United States of America. brian.foster@nih.gov

ABSTRACT

Background: Inorganic pyrophosphate (PP(i)) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PP(i) are controlled by antagonistic functions of factors that decrease PP(i) and promote mineralization (tissue-nonspecific alkaline phosphatase, Alpl/TNAP), and those that increase local PP(i) and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PP(i) in cementum formation, we analyzed root development in knock-out ((-/-)) mice featuring PP(i) dysregulation.

Results: Excess PP(i) in the Alpl(-/-) mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PP(i) in both Ank and Enpp1(-/-) mice significantly increased cementum apposition and overall thickness more than 12-fold vs. controls, while dentin and cellular cementum were unaltered. Though PP(i) regulators are widely expressed, cementoblasts selectively expressed greater ANK and NPP1 along the root surface, and dramatically increased ANK or NPP1 in models of reduced PP(i) output, in compensatory fashion. In vitro mechanistic studies confirmed that under low PP(i) mineralizing conditions, cementoblasts increased Ank (5-fold) and Enpp1 (20-fold), while increasing PP(i) inhibited mineralization and associated increases in Ank and Enpp1 mRNA.

Conclusions: Results from these studies demonstrate a novel developmental regulation of acellular cementum, wherein cementoblasts tune cementogenesis by modulating local levels of PP(i), directing and regulating mineral apposition. These findings underscore developmental differences in acellular versus cellular cementum, and suggest new approaches for cementum regeneration.

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Related in: MedlinePlus

Acellular cementogenesis requires diminution of pyrophosphate.The Alpl+/+ control first molar root at (A) 14 dpn and (C) 21 dpn, shows a normal periodontal architecture with a continuous layer of basophilic cementum (c) covering the root dentin (d) surface. In Alpl−/− molars, ablation of TNAP resulted in (B) hyperosteoidosis (*) and loss of the acellular cementum layer, and (D) a weak cementum-PDL interface, manifested by tearing (#). (E–H) Disrupted localization of cementum markers bone sialoprotein (BSP) and osteopontin (OPN) compared to control supported histological observations of cementum hypoplasia in 14 dpn Alpl−/− mouse molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar = 100 µm.
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pone-0038393-g002: Acellular cementogenesis requires diminution of pyrophosphate.The Alpl+/+ control first molar root at (A) 14 dpn and (C) 21 dpn, shows a normal periodontal architecture with a continuous layer of basophilic cementum (c) covering the root dentin (d) surface. In Alpl−/− molars, ablation of TNAP resulted in (B) hyperosteoidosis (*) and loss of the acellular cementum layer, and (D) a weak cementum-PDL interface, manifested by tearing (#). (E–H) Disrupted localization of cementum markers bone sialoprotein (BSP) and osteopontin (OPN) compared to control supported histological observations of cementum hypoplasia in 14 dpn Alpl−/− mouse molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar = 100 µm.

Mentions: In the infantile form of HPP, the skeleton is properly mineralized at birth, but postnatal skeletogenesis is compromised [7]. Alpl−/− mice phenocopy aspects of infantile HPP, where loss of TNAP was previously reported to have little effect on bone until postnatal day 6 [10], [24]. At 14 dpn, the majority of alveolar and mandibular bone in Alpl−/− mice was well developed, though signs of hyperosteoidosis were noted in the bone adjacent to the molar root (Figure 2A and B). In Alpl+/+ molars, acellular cementum (AEFC) covered the root dentin as a thin and uniform basophilic layer. Alpl−/− molars were marked by disruption of acellular cementum, visible as reduction of the basophilic layer (cementum aplasia or severe hypoplasia) and direct contact of PDL cells and tissues with dentin. By 21 dpn this cementum defect was sometimes associated with tearing at the PDL-AEFC interface, suggesting poor integration of Sharpey's fibers at the root surface (not seen at the PDL-bone interface) (Figure 2C and D) and consistent with HPP case reports observing premature tooth exfoliation. This is not likely to be a processing artifact, as infiltrating cells were present in the tear zone. These results agree with AEFC disruption described in this Alpl−/− model [25], as well as a different TNAP loss-of-function mouse [23].


Central role of pyrophosphate in acellular cementum formation.

Foster BL, Nagatomo KJ, Nociti FH, Fong H, Dunn D, Tran AB, Wang W, Narisawa S, Millán JL, Somerman MJ - PLoS ONE (2012)

Acellular cementogenesis requires diminution of pyrophosphate.The Alpl+/+ control first molar root at (A) 14 dpn and (C) 21 dpn, shows a normal periodontal architecture with a continuous layer of basophilic cementum (c) covering the root dentin (d) surface. In Alpl−/− molars, ablation of TNAP resulted in (B) hyperosteoidosis (*) and loss of the acellular cementum layer, and (D) a weak cementum-PDL interface, manifested by tearing (#). (E–H) Disrupted localization of cementum markers bone sialoprotein (BSP) and osteopontin (OPN) compared to control supported histological observations of cementum hypoplasia in 14 dpn Alpl−/− mouse molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar = 100 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366957&req=5

pone-0038393-g002: Acellular cementogenesis requires diminution of pyrophosphate.The Alpl+/+ control first molar root at (A) 14 dpn and (C) 21 dpn, shows a normal periodontal architecture with a continuous layer of basophilic cementum (c) covering the root dentin (d) surface. In Alpl−/− molars, ablation of TNAP resulted in (B) hyperosteoidosis (*) and loss of the acellular cementum layer, and (D) a weak cementum-PDL interface, manifested by tearing (#). (E–H) Disrupted localization of cementum markers bone sialoprotein (BSP) and osteopontin (OPN) compared to control supported histological observations of cementum hypoplasia in 14 dpn Alpl−/− mouse molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar = 100 µm.
Mentions: In the infantile form of HPP, the skeleton is properly mineralized at birth, but postnatal skeletogenesis is compromised [7]. Alpl−/− mice phenocopy aspects of infantile HPP, where loss of TNAP was previously reported to have little effect on bone until postnatal day 6 [10], [24]. At 14 dpn, the majority of alveolar and mandibular bone in Alpl−/− mice was well developed, though signs of hyperosteoidosis were noted in the bone adjacent to the molar root (Figure 2A and B). In Alpl+/+ molars, acellular cementum (AEFC) covered the root dentin as a thin and uniform basophilic layer. Alpl−/− molars were marked by disruption of acellular cementum, visible as reduction of the basophilic layer (cementum aplasia or severe hypoplasia) and direct contact of PDL cells and tissues with dentin. By 21 dpn this cementum defect was sometimes associated with tearing at the PDL-AEFC interface, suggesting poor integration of Sharpey's fibers at the root surface (not seen at the PDL-bone interface) (Figure 2C and D) and consistent with HPP case reports observing premature tooth exfoliation. This is not likely to be a processing artifact, as infiltrating cells were present in the tear zone. These results agree with AEFC disruption described in this Alpl−/− model [25], as well as a different TNAP loss-of-function mouse [23].

Bottom Line: Though PP(i) regulators are widely expressed, cementoblasts selectively expressed greater ANK and NPP1 along the root surface, and dramatically increased ANK or NPP1 in models of reduced PP(i) output, in compensatory fashion.In vitro mechanistic studies confirmed that under low PP(i) mineralizing conditions, cementoblasts increased Ank (5-fold) and Enpp1 (20-fold), while increasing PP(i) inhibited mineralization and associated increases in Ank and Enpp1 mRNA.These findings underscore developmental differences in acellular versus cellular cementum, and suggest new approaches for cementum regeneration.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Oral Connective Tissue Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, United States of America. brian.foster@nih.gov

ABSTRACT

Background: Inorganic pyrophosphate (PP(i)) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PP(i) are controlled by antagonistic functions of factors that decrease PP(i) and promote mineralization (tissue-nonspecific alkaline phosphatase, Alpl/TNAP), and those that increase local PP(i) and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PP(i) in cementum formation, we analyzed root development in knock-out ((-/-)) mice featuring PP(i) dysregulation.

Results: Excess PP(i) in the Alpl(-/-) mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PP(i) in both Ank and Enpp1(-/-) mice significantly increased cementum apposition and overall thickness more than 12-fold vs. controls, while dentin and cellular cementum were unaltered. Though PP(i) regulators are widely expressed, cementoblasts selectively expressed greater ANK and NPP1 along the root surface, and dramatically increased ANK or NPP1 in models of reduced PP(i) output, in compensatory fashion. In vitro mechanistic studies confirmed that under low PP(i) mineralizing conditions, cementoblasts increased Ank (5-fold) and Enpp1 (20-fold), while increasing PP(i) inhibited mineralization and associated increases in Ank and Enpp1 mRNA.

Conclusions: Results from these studies demonstrate a novel developmental regulation of acellular cementum, wherein cementoblasts tune cementogenesis by modulating local levels of PP(i), directing and regulating mineral apposition. These findings underscore developmental differences in acellular versus cellular cementum, and suggest new approaches for cementum regeneration.

Show MeSH
Related in: MedlinePlus