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• W2789288587 abstract "Pathologic cardiovascular calcification is associated with a number of conditions and is a common complication of chronic kidney disease. Because ambient calcium and phosphate levels together with properties of the vascular matrix favor calcification even under normal conditions, endogenous inhibitors such as pyrophosphate play a key role in prevention. Genetic diseases and animal models have elucidated the metabolism of extracellular pyrophosphate and demonstrated the importance of pyrophosphate deficiency in vascular calcification. Therapies based on pyrophosphate metabolism have been effective in animal models, including renal failure, and hold promise as future therapies to prevent vascular calcification. Pathologic cardiovascular calcification is associated with a number of conditions and is a common complication of chronic kidney disease. Because ambient calcium and phosphate levels together with properties of the vascular matrix favor calcification even under normal conditions, endogenous inhibitors such as pyrophosphate play a key role in prevention. Genetic diseases and animal models have elucidated the metabolism of extracellular pyrophosphate and demonstrated the importance of pyrophosphate deficiency in vascular calcification. Therapies based on pyrophosphate metabolism have been effective in animal models, including renal failure, and hold promise as future therapies to prevent vascular calcification. Pathologic cardiovascular calcification is associated with a number of genetic diseases and common conditions such as diabetes, chronic kidney disease, and aging, and is associated with poor clinical outcomes. This calcification, primarily in the form of hydroxyapatite, occurs in arteries and cardiac valves. In arteries, calcified deposits are distinguished by their location in the arterial wall and their different pathophysiologies. Intimal calcification occurs in advanced atherosclerotic plaques and is associated with inflammation, whereas medial calcification (also called “Monckeberg’s medial sclerosis”) occurs in the medial layer and the internal elastic lamina in the absence of atherosclerosis or inflammation. It is this latter form that is frequently associated with disordered mineral metabolism. Hydroxyapatite (principally carbonated-substituted apatite), which is the main calcium phosphate crystal form found in bone and calcified tissues, is not formed directly from calcium and phosphate ions but rather through a solid-phase reaction through intermediaries such as octacalcium-phosphate and amorphous calcium-phosphate (Figure 1).1O’Neill W.C. The fallacy of the calcium-phosphorus product.Kidney Int. 2007; 72: 792-796Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Amorphous calcium-phosphate, which is also found within calcifications, consists of spherical Ca9(PO4)6 clusters (called “Posner’s clusters”), which appear to be energetically favored compared to Ca3(PO4) and Ca6(PO4)4 clusters. Therefore, the structure of hydroxyapatite and octacalcium-phosphate can be also be interpreted as an aggregation of different clusters in a second step (Figure 1). The precursors of hydroxyapatite derive from the formation of dicalcium-phosphate dihydrate (CaHPO42H20; also called “brushite”), the initial event in the calcification process. Formation of brushite depends on the concentration and forms of calcium and phosphate ions. At physiologic pH, approximately 80% of phosphate is HPO42−, and the remaining 20% is H2PO4−. In addition to ionized calcium, there is also complexed calcium (primarily to citrate and bicarbonate) and protein-bound calcium (primarily to albumin). Based on the activity coefficients of Ca2+ and HPO42− and the solubility product of brushite, and assuming that 47% of total serum calcium is ionized and that 81% of total phosphorus is HPO42−, the product of the total calcium and phosphorus concentrations (Ca X P) in plasma would have to exceed 90 mg2Urry D.W. Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis.Proc Natl Acad Sci U S A. 1971; 68: 810-814Crossref PubMed Scopus (156) Google Scholar/dl2 in order for precipitation to occur. Thus, despite frequent pronouncements to the contrary, extracellular fluid is not supersaturated with respect to calcium and phosphate.1O’Neill W.C. The fallacy of the calcium-phosphorus product.Kidney Int. 2007; 72: 792-796Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Because bone mineralization and ectopic calcification clearly occur at a lower Ca X P, including in patients with chronic kidney disease, it is clear that a process must exist for calcification to occur below the solubility product of brushite. This is mediated by matrix proteins that essentially catalyze this reaction.2Urry D.W. Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis.Proc Natl Acad Sci U S A. 1971; 68: 810-814Crossref PubMed Scopus (156) Google Scholar According to the charge neutralization theory of calcification, the high glycine content of these matrix proteins favors the formation of beta-turns which bind calcium ions nonionically, enabling phosphate to bind the calcium in a configuration that favors apatite formation under physiologic conditions (Figure 1).2Urry D.W. Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis.Proc Natl Acad Sci U S A. 1971; 68: 810-814Crossref PubMed Scopus (156) Google Scholar In bone and arteries, this process occurs predominantly on Type I collagen and elastic fibers, respectively. Any proposed mechanism of vascular calcification, including osteochondrogenic differentiation or apoptosis of vascular smooth muscle, must take this chemistry into account. Recent studies demonstrate that calcium-phosphate deposits can induce the transition to a bone-forming phenotype as well as apoptosis in vascular smooth muscle cells, suggesting that these processes may instead be a result of the initial calcification.3Villa-Bellosta R. Millan A. Sorribas V. Role of calcium-phosphate deposition in vascular smooth muscle cell calcification.Am J Physiol Cell Physiol. 2011; 300: C210-C220Crossref PubMed Scopus (128) Google Scholar It is clear, then, that mineralization, including vascular calcification, can occur at physiological calcium and phosphate concentrations and that inhibitory mechanisms must be in place to restrict this to bone and cartilage. A number of genetic diseases and animal models have identified endogenous inhibitors of calcification that are required to prevent vascular calcification under normal conditions. These include proteins such as the matrix Gla protein, fetuin-A, and osteopontin and the low-molecular-weight compound pyrophosphate. Pathologic calcification occurs when inhibitors are deficient or when over-whelmed by factors such as hyperphosphatemia. When the solubility product for CaHPO4 is actually exceeded, precipitation in the circulation is prevented by binding of fetuin-A to nascent crystals to form colloidal calcium-phosphate (also termed “calciprotein” particles), which is then cleared by the reticuloendothelial system. Pyrophosphate is a potent inhibitor of calcium crystallization and deposition that has long been used industrially for this purpose and is the active ingredient in plaque-preventing toothpaste. It acts by avidly binding to nascent hydroxyapatite crystals, being sequestered in the process,4Meyer J.L. Can biological calcification occur in the presence of pyrophosphate?.Arch Biochem Biophys. 1984; 231: 1-8Crossref PubMed Scopus (173) Google Scholar with complete inhibition at micromolar concentrations that are more than 1,000-fold less than physiologic calcium or phosphate concentrations.4Meyer J.L. Can biological calcification occur in the presence of pyrophosphate?.Arch Biochem Biophys. 1984; 231: 1-8Crossref PubMed Scopus (173) Google Scholar, 5Villa-Bellosta R. Sorribas V. Calcium phosphate deposition with normal phosphate concentration: role of pyrophosphate.Circ J. 2011; 75: 2705-2710Crossref PubMed Scopus (48) Google Scholar Extracellular pyrophosphate is present at levels sufficient to completely prevent hydroxyapatite formation and, although there is local production by vascular smooth muscle,6Villa-Bellosta R. Wang X. Millán J.L. et al.Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle.Am J Physiol Heart Circ Physiol. 2011; 301: H61-H68Crossref PubMed Scopus (108) Google Scholar it is the circulating pyrophosphate that is primarily responsible for inhibiting calcification.7Lomashvili K.A. Narisawa S. Millán J.L. et al.Vascular calcification is dependent on plasma levels of pyrophosphate.Kidney Int. 2014; 85: 1351-1356Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Its ability to prevent vascular calcification was originally demonstrated in an animal model of vitamin D toxicity8Schibler D. Russell R.G. Fleisch H. Inhibition by pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats.Clin Sci. 1968; 35: 363-372PubMed Google Scholar and subsequently in aortic rings and aortic valves in culture.9Rathan S. Yoganathan A.P. O’Neill C.W. The role of inorganic pyrophosphate in aortic valve calcification.J Heart Valve Dis. 2014; 23: 387-394PubMed Google Scholar, 10Lomashvili K.A. Cobbs S. Hennigar R.A. et al.Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin.J Am Soc Nephrol. 2004; 15: 1392-1401Crossref PubMed Scopus (255) Google Scholar This action is mimicked by various polyphosphates including bisphosphonates,11Villa-Bellosta R. Sorribas V. Prevention of vascular calcification by polyphosphates and nucleotides: role of ATP.Circ J. 2013; 77: 2145-2151Crossref PubMed Scopus (31) Google Scholar, 12Francis M.D. Russell R.G. Fleisch H. Diphosphonates inhibit formation of calcium-phosphate crystals in vitro and pathological calcification in vivo.Science. 1969; 165: 1264-1266Crossref PubMed Scopus (487) Google Scholar, 13Lomashvili K.A. Monier-Faugere M.C. Wang X. et al.Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure.Kidney Int. 2009; 75: 617-625Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar which were originally developed as nonhydrolyzable pyrophosphate analogs to prevent ectopic calcification. A normal pyrophosphate concentration is sufficient to prevent calcification when the phosphate concentration is in the normal range but may not be sufficient in the face of hyperphosphatemia.5Villa-Bellosta R. Sorribas V. Calcium phosphate deposition with normal phosphate concentration: role of pyrophosphate.Circ J. 2011; 75: 2705-2710Crossref PubMed Scopus (48) Google Scholar Pyrophosphate may also contribute to the inhibition of calcium-phosphate precipitation in the circulation as serum levels correlate with the formation of calciprotein particles in vitro.14Smith E.R. Ford M.L. Tomlinson L.A. et al.Serum calcification propensity predicts all-cause mortality in predialysis CKD.J Am Soc Nephrol. 2014; 25: 339-348Crossref PubMed Scopus (151) Google Scholar Extracellular pyrophosphate is a product of the enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1), which hydrolyzes extracellular ATP to generate AMP and pyrophosphate (Figure 2). eNPP1 is the principal source of circulating pyrophosphate,7Lomashvili K.A. Narisawa S. Millán J.L. et al.Vascular calcification is dependent on plasma levels of pyrophosphate.Kidney Int. 2014; 85: 1351-1356Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar as well as extracellular pyrophosphate in vascular smooth muscle cells and aortas in culture.6Villa-Bellosta R. Wang X. Millán J.L. et al.Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle.Am J Physiol Heart Circ Physiol. 2011; 301: H61-H68Crossref PubMed Scopus (108) Google Scholar, 7Lomashvili K.A. Narisawa S. Millán J.L. et al.Vascular calcification is dependent on plasma levels of pyrophosphate.Kidney Int. 2014; 85: 1351-1356Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar The membrane protein ANK can transport pyrophosphate and also has been proposed as a source of extracellular pyrophosphate from intracellular pyrophosphate.15Ho A.M. Johnson M.D. Kingsley D.M. Role of the mouse ank gene in control of tissue calcification and arthritis.Science. 2000; 289: 265-270Crossref PubMed Scopus (545) Google Scholar However, it does not appear to transport pyrophosphate under physiologic conditions6Villa-Bellosta R. Wang X. Millán J.L. et al.Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle.Am J Physiol Heart Circ Physiol. 2011; 301: H61-H68Crossref PubMed Scopus (108) Google Scholar and more likely contributes to extracellular pyrophosphate by providing substrate to eNPP1 through transport of ATP out of cells. ATP can also be released through exocytotic mechanisms and by membrane transporters, including connexin hemichannels, pannexin, cystic fibrosis transmembrane conductance regulator, the multidrug resistance gene product mdr (P-glycoprotein), and the sulfonylurea receptor. Which of these is the principal supplier of ATP for eNPP1 is unknown and likely varies among tissues. The tissue source of circulating pyrophosphate is unknown, but recent data implicate the liver.16Jansen R.S. Duijst S. Mahakena S. et al.ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.Arterioscler Thromb Vasc Biol. 2014; 34: 1985-1989Crossref PubMed Scopus (202) Google Scholar The production here appears to be dependent on the membrane protein ATP-binding cassette subfamily C member 6 (ABCC6), although this protein does not transport ATP. Pyrophosphate is degraded to phosphate enzymatically by tissue-nonspecific alkaline phosphatase (TNAP), which plays a key role in determining pyrophosphate levels and calcification (Figure 2). The importance of TNAP was demonstrated in a seminal study showing that coexpression of TNAP and Type I collagen in nonosseous tissue is sufficient to induce mineralization.17Murshed M. Harmey D. Millán J.L. et al.Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone.Genes Dev. 2005; 19: 1093-1104Crossref PubMed Scopus (482) Google Scholar Thus, it is the high expression of TNAP in bone that allows mineralization to proceed by eliminating pyrophosphate locally. Consistent with this, over-expression of TNAP increases skeletal mineralization in vivo,18Narisawa S. Yadav M.C. Millán J.L. In vivo over-expression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin.J Bone Miner Res. 2013; 28: 1587-1598Crossref PubMed Scopus (92) Google Scholar whereas bone formation is defective in humans lacking this enzyme (hypophosphatasia) and in the corresponding mouse model. These patients also have elevated extracellular pyrophosphate levels. Over-expression of TNAP in aortic rings ex vivo6Villa-Bellosta R. Wang X. Millán J.L. et al.Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle.Am J Physiol Heart Circ Physiol. 2011; 301: H61-H68Crossref PubMed Scopus (108) Google Scholar and selectively in smooth muscle in vivo19Sheen C.R. Kuss P. Narisawa S. et al.Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification.J Bone Miner Res. 2015; 30: 824-836Crossref PubMed Scopus (146) Google Scholar are sufficient to induce medial vascular calcification, with the latter being the most robust genetic mouse model of vascular calcification to date. Inhibitors of TNAP can prevent vascular calcification in vitro20Narisawa S. Harmey D. Yadav M.C. et al.Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification.J Bone Miner Res. 2007; 22: 1700-1710Crossref PubMed Scopus (178) Google Scholar and in a mouse model of pseudoxanthoma elasticum.21Ziegler S.G. Ferreira C.R. MacFarlane E.G. et al.Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase.Sci Transl Med. 2017; 9Crossref Scopus (64) Google Scholar Pyrophosphate deficiency is the basis for vascular calcification in several genetic disorders. These disorders illustrate the important role of pyrophosphate in vivo and have provided important insights into its metabolism. The most dramatic of these is generalized arterial calcification of infancy,22Rutsch F. Ruf N. Vaingankar S. et al.Mutations in ENPP1 are associated with “idiopathic” infantile arterial calcification.Nat Genet. 2003; 34: 379-381Crossref PubMed Scopus (470) Google Scholar which is due to mutations in eNPP1 and results in severe calcification of the media and internal elastic lamina of large and medium-sized arteries that is often present at birth. A similar phenotype occurs in eNPP1-null mice,23Johnson K. Polewski M. van Etten D. et al.Chondrogenesis mediated by PPi depletion promotes spontaneous aortic calcification in NPP1−/− mice.Arterioscler Thromb Vasc Biol. 2005; 25: 686-691Crossref PubMed Scopus (154) Google Scholar and plasma pyrophosphate levels are very low in both the patients and the mouse model.22Rutsch F. Ruf N. Vaingankar S. et al.Mutations in ENPP1 are associated with “idiopathic” infantile arterial calcification.Nat Genet. 2003; 34: 379-381Crossref PubMed Scopus (470) Google Scholar, 23Johnson K. Polewski M. van Etten D. et al.Chondrogenesis mediated by PPi depletion promotes spontaneous aortic calcification in NPP1−/− mice.Arterioscler Thromb Vasc Biol. 2005; 25: 686-691Crossref PubMed Scopus (154) Google Scholar Plasma pyrophosphate levels are also low in pseudoxanthoma elasticum, a heritable connective tissue disorder due to mutations in the ABCC6 and characterized by testicular microlithiasis and calcification of the elastic fibers in the skin, arteries, and retinas. This disorder is partially recreated in mice in which ABCC6 has been genetically deleted. This membrane protein is present primarily in liver, and pyrophosphate production by liver is reduced in these mice due to impaired release of ATP.16Jansen R.S. Duijst S. Mahakena S. et al.ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.Arterioscler Thromb Vasc Biol. 2014; 34: 1985-1989Crossref PubMed Scopus (202) Google Scholar However, ABCC6 does not transport ATP or pyrophosphate, and its mechanism of action remains unclear. Mice with a spontaneous mutation in the ank gene develop progressive ankylosis due to calcification as well as medial arterial calcification with a high-phosphate diet.24Harmey D. Hessle L. Narisawa S. et al.Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders.Am J Pathol. 2004; 164: 1199-1209Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar The product of this gene is the ANK membrane protein that can transport pyrophosphate in vitro.13Lomashvili K.A. Monier-Faugere M.C. Wang X. et al.Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure.Kidney Int. 2009; 75: 617-625Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Cells cultured from these mice display lower levels of extracellular pyrophosphate, and ANK over-expression results in higher extracellular pyrophosphate levels.13Lomashvili K.A. Monier-Faugere M.C. Wang X. et al.Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure.Kidney Int. 2009; 75: 617-625Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Mutations in ANK in humans result in craniometaphyseal dysplasia,25Nürnberg P. Thiele H. Chandler D. et al.Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia.Nat Genet. 2001; 28: 37-41Crossref PubMed Scopus (164) Google Scholar a rare skeletal condition characterized by increased density of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones but not vascular calcification. Finally, a mouse model of Hutchinson-Gilford progeria syndrome, a genetic disorder characterized by vascular calcification, shows reduction in the synthesis of extracellular pyrophosphate due to alterations in its metabolism, including impaired ATP synthesis and increased TNAP expression and activity.26Villa-Bellosta R. Rivera-Torres J. Osorio F.G. et al.Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment.Circulation. 2013; 127: 2442-2451Crossref PubMed Scopus (156) Google Scholar Daily i.p. injections of exogenous pyrophosphate also prevented the calcification.26Villa-Bellosta R. Rivera-Torres J. Osorio F.G. et al.Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment.Circulation. 2013; 127: 2442-2451Crossref PubMed Scopus (156) Google Scholar Vascular calcification is common in patients with chronic kidney disease and particularly end-stage renal disease and is also seen in animal models of renal failure. Circulating pyrophosphate levels are reduced in hemodialysis patients, and because pyrophosphate is removed by dialysis, levels decrease after dialysis.27Lomashvili K.A. Khawandi W. O’Neill W.C. Reduced plasma pyrophosphate levels in hemodialysis patients.J Am Soc Nephrol. 2005; 16: 2495-2500Crossref PubMed Scopus (152) Google Scholar The increased expression and activity of TNAP in vascular smooth muscle noted in uremic rats may contribute this deficiency.28Lomashvili K.A. Garg P. Narisawa S. et al.Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification.Kidney Int. 2008; 73: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar Furthermore, TNAP activity is increased in postdialysis plasma, which is due in part to the increase in pH and reduction in phosphate levels, both of which directly increase the activity of the enzyme.29Villa-Bellosta R. González-Parra E. Egido J. Alkalosis and dialytic clearance of phosphate increases phosphatase activity: a hidden consequence of hemodialysis.PLoS One. 2016; 11: e0159858Crossref PubMed Scopus (13) Google Scholar Removal of other uremic compounds could also enhance TNAP activity. A reduction in ABCC6 has also been reported in uremic animals.30Lau W.L. Liu S. Vaziri N.D. Chronic kidney disease results in deficiency of ABCC6, the novel inhibitor of vascular calcification.Am J Nephrol. 2014; 40: 51-55Crossref PubMed Scopus (19) Google Scholar These data suggest that pyrophosphate may be a useful therapy for vascular calcification, but because pyrophosphate is a direct inhibitor of calcification, inhibition of bone mineralization is a potential side effect. Administration of pyrophosphate can prevent calcification in animal models of renal failure without inhibition of bone formation,31O’Neill W.C. Lomashvili K.A. Malluche H.H. et al.Treatment with pyrophosphate inhibits uremic vascular calcification.Kidney Int. 2011; 79: 512-517Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 32Riser B.L. Barreto F.C. Rezq R. et al.Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia.Nephrol Dial Transplant. 2011; 26: 3349-3357Crossref PubMed Scopus (55) Google Scholar and the lack of effect on bone is probably explained by the high level of TNAP in this tissue. Unfortunately, pyrophosphate is hydrolyzed in the stomach and must be given parenterally, and its half-life is less than 30 min in plasma.31O’Neill W.C. Lomashvili K.A. Malluche H.H. et al.Treatment with pyrophosphate inhibits uremic vascular calcification.Kidney Int. 2011; 79: 512-517Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar The latter problem can be avoided with bisphosphonates, which inhibit uremic vascular calcification in animals at doses far lower than those for pyrophosphate.13Lomashvili K.A. Monier-Faugere M.C. Wang X. et al.Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure.Kidney Int. 2009; 75: 617-625Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar However, this was paralleled by a decrease in bone formation, which is consistent with the osteomalacia that can occur with these compounds and is explained by their resistance to hydrolysis by TNAP in bone. Pyrophosphate is a major endogenous inhibitor of calcification, and its metabolism plays a key role in vascular calcification, including in patients with chronic kidney disease. The use of pyrophosphate as a therapeutic agent is limited by its pharmacokinetics and the fact that stable analogs inhibit bone formation. However, strategies to raise pyrophosphate levels by targeting its metabolism (e.g., administration of TNAP inhibitors or eNPP1) may have promise as therapies in the future." @default.
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