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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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Pyrophosphate homeostasis in the extracellular space.Inorganic phosphate (Pi) is a component of mineral hydroxyapatite (HAP), while pyrophosphate (PPi) is a potent inhibitor of HAP crystal precipitation and growth. The enzyme tissue nonspecific alkaline phosphatase (TNAP) hydrolyzes PPi to release ionic Pi, creating conditions conducive for mineralization. Local PPi is increased by the functions of the progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which act to keep the mineralization process in check.
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pone-0038393-g001: Pyrophosphate homeostasis in the extracellular space.Inorganic phosphate (Pi) is a component of mineral hydroxyapatite (HAP), while pyrophosphate (PPi) is a potent inhibitor of HAP crystal precipitation and growth. The enzyme tissue nonspecific alkaline phosphatase (TNAP) hydrolyzes PPi to release ionic Pi, creating conditions conducive for mineralization. Local PPi is increased by the functions of the progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which act to keep the mineralization process in check.

Mentions: Local tissue concentrations of PPi are controlled by a number of regulatory enzymes and transporters. Tissue nonspecific alkaline phosphatase (TNAP) is an ectoenzyme capable of hydrolyzing PPi and providing Pi[6]. TNAP is expressed by mineralizing cells of bones and teeth, and is critical for proper skeletal mineralization [5], [7]. Hydrolysis by alkaline phosphatase activity (ALP) thus provides a mechanism for clearance of PPi, allowing mineralization to proceed. Loss of function mutations in the TNAP gene Alpl cause hypophosphatasia (HPP), a disease marked by poor bone mineralization, rickets, and osteomalacia, as well as tooth phenotypes [8], [9]. Ablation of the homologous mouse gene Alpl (formerly Akp2) produces a phenotype consistent with increased PPi and mineralization disorders of infantile HPP [10], [11]. Conversely, two factors have been identified which increase local PPi in tissues. The progressive ankylosis gene (Ank; Ankh in humans) encodes a multipass transmembrane protein that regulates transport of intracellular PPi to the extracellular space [12]–[14]. Ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1; encoded by the Enpp1 gene) also works to increase extracellular PPi by hydrolysis of nucleotide triphosphates [15]. PPi removal by ALP activity thus antagonizes provision of PPi by ANK and NPP1, thereby creating a concerted regulation of Pi and PPi levels (Figure 1), and ultimately, mineralization [16], [17].


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)

Pyrophosphate homeostasis in the extracellular space.Inorganic phosphate (Pi) is a component of mineral hydroxyapatite (HAP), while pyrophosphate (PPi) is a potent inhibitor of HAP crystal precipitation and growth. The enzyme tissue nonspecific alkaline phosphatase (TNAP) hydrolyzes PPi to release ionic Pi, creating conditions conducive for mineralization. Local PPi is increased by the functions of the progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which act to keep the mineralization process in check.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038393-g001: Pyrophosphate homeostasis in the extracellular space.Inorganic phosphate (Pi) is a component of mineral hydroxyapatite (HAP), while pyrophosphate (PPi) is a potent inhibitor of HAP crystal precipitation and growth. The enzyme tissue nonspecific alkaline phosphatase (TNAP) hydrolyzes PPi to release ionic Pi, creating conditions conducive for mineralization. Local PPi is increased by the functions of the progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which act to keep the mineralization process in check.
Mentions: Local tissue concentrations of PPi are controlled by a number of regulatory enzymes and transporters. Tissue nonspecific alkaline phosphatase (TNAP) is an ectoenzyme capable of hydrolyzing PPi and providing Pi[6]. TNAP is expressed by mineralizing cells of bones and teeth, and is critical for proper skeletal mineralization [5], [7]. Hydrolysis by alkaline phosphatase activity (ALP) thus provides a mechanism for clearance of PPi, allowing mineralization to proceed. Loss of function mutations in the TNAP gene Alpl cause hypophosphatasia (HPP), a disease marked by poor bone mineralization, rickets, and osteomalacia, as well as tooth phenotypes [8], [9]. Ablation of the homologous mouse gene Alpl (formerly Akp2) produces a phenotype consistent with increased PPi and mineralization disorders of infantile HPP [10], [11]. Conversely, two factors have been identified which increase local PPi in tissues. The progressive ankylosis gene (Ank; Ankh in humans) encodes a multipass transmembrane protein that regulates transport of intracellular PPi to the extracellular space [12]–[14]. Ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1; encoded by the Enpp1 gene) also works to increase extracellular PPi by hydrolysis of nucleotide triphosphates [15]. PPi removal by ALP activity thus antagonizes provision of PPi by ANK and NPP1, thereby creating a concerted regulation of Pi and PPi levels (Figure 1), and ultimately, mineralization [16], [17].

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