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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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Increased cementum apposition in Ank and Enpp1−/− teeth.(A) During early root formation between 14 and 26 dpn, both Ank and Enpp1−/− molars featured at least 10-fold greater cementogenesis compared to controls. From 26 to 60 dpn, Ank and Enpp1−/− cementum continued to increase at a rate of 0.2–0.7 µm/day, while Ank and Enpp1+/+ controls featured tightly controlled apposition at the pace of 0.01–0.05 µm/day. (B) Histomorphometry confirmed Ank or Enpp1−/− cervical cementum was significantly increased compared to controls, while PDL width was maintained and alveolar bone thickness tended towards reduction. Values with the same letter were not significantly different, while different letters indicate a statistically significant intergroup (genotype) difference (p<0.05) as tested by ANOVA followed by the Tukey test for direct pair-wise comparisons.
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pone-0038393-g005: Increased cementum apposition in Ank and Enpp1−/− teeth.(A) During early root formation between 14 and 26 dpn, both Ank and Enpp1−/− molars featured at least 10-fold greater cementogenesis compared to controls. From 26 to 60 dpn, Ank and Enpp1−/− cementum continued to increase at a rate of 0.2–0.7 µm/day, while Ank and Enpp1+/+ controls featured tightly controlled apposition at the pace of 0.01–0.05 µm/day. (B) Histomorphometry confirmed Ank or Enpp1−/− cervical cementum was significantly increased compared to controls, while PDL width was maintained and alveolar bone thickness tended towards reduction. Values with the same letter were not significantly different, while different letters indicate a statistically significant intergroup (genotype) difference (p<0.05) as tested by ANOVA followed by the Tukey test for direct pair-wise comparisons.

Mentions: Both Ank and Enpp1−/− mice featured a hypercementosis phenotype, indicating both PPi regulators function in controlling cementum formation. Comparative analysis between Ank and Enpp1−/− and their respective controls was accomplished by measuring the growth rate of cervical cementum over time. During early root formation between 14 and 26 dpn, Ank and Enpp1−/− molars featured at least 10-fold greater cementogenesis compared to controls (Figure 5A). Ank and Enpp1−/− cementum continued to increase at a rate of 0.2–0.7 µm/day from 26 to 60 dpn, while over the same period, controls featured tightly controlled apposition, growing at the much slower pace of 0.01–0.05 µm/day.


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)

Increased cementum apposition in Ank and Enpp1−/− teeth.(A) During early root formation between 14 and 26 dpn, both Ank and Enpp1−/− molars featured at least 10-fold greater cementogenesis compared to controls. From 26 to 60 dpn, Ank and Enpp1−/− cementum continued to increase at a rate of 0.2–0.7 µm/day, while Ank and Enpp1+/+ controls featured tightly controlled apposition at the pace of 0.01–0.05 µm/day. (B) Histomorphometry confirmed Ank or Enpp1−/− cervical cementum was significantly increased compared to controls, while PDL width was maintained and alveolar bone thickness tended towards reduction. Values with the same letter were not significantly different, while different letters indicate a statistically significant intergroup (genotype) difference (p<0.05) as tested by ANOVA followed by the Tukey test for direct pair-wise comparisons.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038393-g005: Increased cementum apposition in Ank and Enpp1−/− teeth.(A) During early root formation between 14 and 26 dpn, both Ank and Enpp1−/− molars featured at least 10-fold greater cementogenesis compared to controls. From 26 to 60 dpn, Ank and Enpp1−/− cementum continued to increase at a rate of 0.2–0.7 µm/day, while Ank and Enpp1+/+ controls featured tightly controlled apposition at the pace of 0.01–0.05 µm/day. (B) Histomorphometry confirmed Ank or Enpp1−/− cervical cementum was significantly increased compared to controls, while PDL width was maintained and alveolar bone thickness tended towards reduction. Values with the same letter were not significantly different, while different letters indicate a statistically significant intergroup (genotype) difference (p<0.05) as tested by ANOVA followed by the Tukey test for direct pair-wise comparisons.
Mentions: Both Ank and Enpp1−/− mice featured a hypercementosis phenotype, indicating both PPi regulators function in controlling cementum formation. Comparative analysis between Ank and Enpp1−/− and their respective controls was accomplished by measuring the growth rate of cervical cementum over time. During early root formation between 14 and 26 dpn, Ank and Enpp1−/− molars featured at least 10-fold greater cementogenesis compared to controls (Figure 5A). Ank and Enpp1−/− cementum continued to increase at a rate of 0.2–0.7 µm/day from 26 to 60 dpn, while over the same period, controls featured tightly controlled apposition, growing at the much slower pace of 0.01–0.05 µm/day.

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