Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone

Russell, R. G. G.; Bisaz, S.; Donath, A; Morgan, D. V.; Fleisch, H.

doi:10.1172/jci106589

Cited by 225 publications

(120 citation statements)

References 19 publications

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“…The importance of PP i as a physiologic inhibitor of mineralization is evident from the skeletal and dental hypomineralization observed in patients with hypophosphatasia attributable to impaired TNAP activity. These patients, as well as Akp2 Ϫ/Ϫ knock-out mice, demonstrate elevated plasma PP i levels in the absence of TNAP enzymatic activity (6,13). Indeed, the bone and tooth hypomineralization of Akp2 Ϫ/Ϫ mice is normalized in Akp2 Ϫ/Ϫ ;Enpp1 Ϫ/Ϫ double-knock-out mice (36,46), suggesting that homeostatic regulation of PP i levels by antagonistic Tnap enzyme activity modulates hydroxyapatite formation in these tissues.…”

Section: Discussionmentioning

confidence: 90%

“…Extracellular PP i deficiency leads to excess hydroxyapatite formation in the skeleton (11), whereas PP i elevation results in decreased skeletal mineralization (6,(12)(13)(14) and the formation of calcium pyrophosphate dihydrate crystals in joints (15,16). The homeostatic regulation of local PP i levels by bone cells is thus an important part of their function related to mineralization.…”

mentioning

confidence: 99%

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Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Addison

Azari

Sørensen

et al. 2007

Journal of Biological Chemistry

333

267

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Inorganic pyrophosphate (PP i ) produced by cells inhibits mineralization by binding to crystals. Its ubiquitous presence is thought to prevent "soft" tissues from mineralizing, whereas its degradation to P i in bones and teeth by tissue-nonspecific alkaline phosphatase (Tnap, Tnsalp, Alpl, Akp2) may facilitate crystal growth. Whereas the crystal binding properties of PP i are largely understood, less is known about its effects on osteoblast activity. We have used MC3T3-E1 osteoblast cultures to investigate the effect of PP i on osteoblast function and matrix mineralization. Mineralization in the cultures was dose-dependently inhibited by PP i . This inhibition could be reversed by Tnap, but not if PP i was bound to mineral. PP i also led to increased levels of osteopontin (Opn) induced via the Erk1/2 and p38 MAPK signaling pathways. Opn regulation by PP i was also insensitive to foscarnet (an inhibitor of phosphate uptake) and levamisole (an inhibitor of Tnap enzymatic activity), suggesting that increased Opn levels did not result from changes in phosphate. Exogenous OPN inhibited mineralization, but dephosphorylation by Tnap reversed this effect, suggesting that OPN inhibits mineralization via its negatively charged phosphate residues and that like PP i , hydrolysis by Tnap reduces its mineral inhibiting potency. Using enzyme kinetic studies, we have shown that PP i inhibits Tnap-mediated P i release from ␤-glycerophosphate (a commonly used source of organic phosphate for culture mineralization studies) through a mixed type of inhibition. In summary, PP i prevents mineralization in MC3T3-E1 osteoblast cultures by at least three different mechanisms that include direct binding to growing crystals, induction of Opn expression, and inhibition of Tnap activity.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Addison

Azari

Sørensen

et al. 2007

Journal of Biological Chemistry

333

267

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“…The plasma concentration of pyrophosphate is reported to be in the range 1-6µM/litre [103]. However, the tissue source of circulating pyrophosphate remains the subject of some debate.…”

Section: Circulating Pyrophosphatementioning

confidence: 99%

Pyrophosphate: a key inhibitor of mineralisation

Orriss

Arnett

Russell

2016

Current Opinion in Pharmacology

140

105

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“…Treatment with magnesium oxide for varying periods produced no alteration of bone surface activity in three patients with osteogenesis imperfecta. Until the significance of the reported metabolic alterations has been more clearly defined, the justification for magnesium oxide treatment is open to question; subsequent investigations have been unable to corroborate the reported leukocyte [12] and pyrophosphate [46] abnormalities in osteogenesis imperfecta.…”

Section: Discussionmentioning

confidence: 99%

Osteogenesis Imperfecta: Morphologic and Biochemical Studies of Connective Tissue

1973

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ExtractIn iliac crest biopsies from 11 patients (ages from 4 to 22 years) with osteogenesis imperfecta, cortical thickness, osteoid width, and number of osteons were less than normal at all ages. Bone surface activity (formation and resorption), measured by quantitative microradiography, was lower than normal in younger patients; the normal pubertal decrease in surface activity was not evident in patients with osteogenesis imperfecta and, consequently, bone surface activity in the older patients was higher than in age-matched normal subjects. The ultrastructure of osteocytes, bone collagen, and scleral collagen did not differ from normal; corneal collagen fibers, however, were approximately half the diameter of normal. Total urinary hydroxyproline excretion, measured in 11 patients, was below normal in all except 2 infants (less than 12 months old). Serum parathyroid hormone levels, measured in nine patients, were normal. Long term treatment with sodium fluoride (two patients) and. treatment with magnesium oxide (three patients) did not alter bone morphology or bone surface activity. SpeculationThe supposition that in osteogenesis imperfecta the connective tissue is characterized by an immature form of collagen was not substantiated by this study. The abnormal fibrillar pattern and paucity of collagen in various connective tissues suggest a qualitative defect, related to collagen maturation, as well as a quantitative deficit in the amount of collagen produced.

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Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone

Cited by 225 publications

References 19 publications

Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Pyrophosphate: a key inhibitor of mineralisation

Osteogenesis Imperfecta: Morphologic and Biochemical Studies of Connective Tissue

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