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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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Attenuation of pyrophosphate increases acellular cementum.The cervical cementum (c) is a thin, acellular layer in Ank; Enpp1+/+ control molars at (A) 14 dpn and (D) 26 dpn, while the (G) apical cementum is thicker and contains cementocytes. Knock-out of either Ank or Enpp1 results in expanded cervical cementum compared to control, visible by 14 dpn (B and C), and progressively thicker by 26 dpn (E and F). In contrast, the apical cementum in Ank and Enpp1−/− molars (H and I) was not different from +/+ control. (J–L) Acellular cementum of the incisor lingual root analog was similarly expanded in Ank and Enpp1−/− vs. control. (M–R) Hypercementosis resulting from loss of ANK was confirmed on all three mandibular molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar for A–L represents 200 µm, and for M–R represents 400 µm.
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pone-0038393-g004: Attenuation of pyrophosphate increases acellular cementum.The cervical cementum (c) is a thin, acellular layer in Ank; Enpp1+/+ control molars at (A) 14 dpn and (D) 26 dpn, while the (G) apical cementum is thicker and contains cementocytes. Knock-out of either Ank or Enpp1 results in expanded cervical cementum compared to control, visible by 14 dpn (B and C), and progressively thicker by 26 dpn (E and F). In contrast, the apical cementum in Ank and Enpp1−/− molars (H and I) was not different from +/+ control. (J–L) Acellular cementum of the incisor lingual root analog was similarly expanded in Ank and Enpp1−/− vs. control. (M–R) Hypercementosis resulting from loss of ANK was confirmed on all three mandibular molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar for A–L represents 200 µm, and for M–R represents 400 µm.

Mentions: Both Ank and Enpp1−/− mice are deficient in extracellular PPi, though by different mechanisms. In molars of both mice at 14 dpn, the developing cervical cementum was expanded (hypercementosis) compared to Ank and Enpp1+/+ controls (Figure 4A–C). At the completion of root development at 26 dpn, both Ank and Enpp1−/− molars featured a nearly identical cementum phenotype where cervical cementum width was expanded several fold over controls (Figure 4D–F). This thick cervical cementum included numerous cell inclusions in the matrix, in a region that is typically acellular type cementum (AEFC). Intriguingly, for both homozygous knock-out models, apical cementum (CIFC) was not morphologically different from controls (Figure 4G–I), PDL space remained unmineralized, and dentin was not altered compared to Ank and Enpp1+/+ mice.


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)

Attenuation of pyrophosphate increases acellular cementum.The cervical cementum (c) is a thin, acellular layer in Ank; Enpp1+/+ control molars at (A) 14 dpn and (D) 26 dpn, while the (G) apical cementum is thicker and contains cementocytes. Knock-out of either Ank or Enpp1 results in expanded cervical cementum compared to control, visible by 14 dpn (B and C), and progressively thicker by 26 dpn (E and F). In contrast, the apical cementum in Ank and Enpp1−/− molars (H and I) was not different from +/+ control. (J–L) Acellular cementum of the incisor lingual root analog was similarly expanded in Ank and Enpp1−/− vs. control. (M–R) Hypercementosis resulting from loss of ANK was confirmed on all three mandibular molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar for A–L represents 200 µm, and for M–R represents 400 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038393-g004: Attenuation of pyrophosphate increases acellular cementum.The cervical cementum (c) is a thin, acellular layer in Ank; Enpp1+/+ control molars at (A) 14 dpn and (D) 26 dpn, while the (G) apical cementum is thicker and contains cementocytes. Knock-out of either Ank or Enpp1 results in expanded cervical cementum compared to control, visible by 14 dpn (B and C), and progressively thicker by 26 dpn (E and F). In contrast, the apical cementum in Ank and Enpp1−/− molars (H and I) was not different from +/+ control. (J–L) Acellular cementum of the incisor lingual root analog was similarly expanded in Ank and Enpp1−/− vs. control. (M–R) Hypercementosis resulting from loss of ANK was confirmed on all three mandibular molars. Abbreviations: d = dentin; c = acellular cementum; p = periodontal ligament; b = bone. Scale bar for A–L represents 200 µm, and for M–R represents 400 µm.
Mentions: Both Ank and Enpp1−/− mice are deficient in extracellular PPi, though by different mechanisms. In molars of both mice at 14 dpn, the developing cervical cementum was expanded (hypercementosis) compared to Ank and Enpp1+/+ controls (Figure 4A–C). At the completion of root development at 26 dpn, both Ank and Enpp1−/− molars featured a nearly identical cementum phenotype where cervical cementum width was expanded several fold over controls (Figure 4D–F). This thick cervical cementum included numerous cell inclusions in the matrix, in a region that is typically acellular type cementum (AEFC). Intriguingly, for both homozygous knock-out models, apical cementum (CIFC) was not morphologically different from controls (Figure 4G–I), PDL space remained unmineralized, and dentin was not altered compared to Ank and Enpp1+/+ mice.

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