1932

Abstract

The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 () codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.

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2024-01-24
2024-04-17
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Literature Cited

  1. 1.
    Zalatan JG, Fenn TD, Brunger AT, Herschlag D. 2006. Structural and functional comparisons of nucleotide pyrophosphatase/phosphodiesterase and alkaline phosphatase: implications for mechanism and evolution. Biochemistry 45:329788–803
    [Google Scholar]
  2. 2.
    Li L, Yin Q, Kuss P, Maliga Z, Millan JL, Wu H, Mitchison TJ. 2014. Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat. Chem. Biol. 10:121043–48
    [Google Scholar]
  3. 3.
    Fleisch H, Bisaz S. 1962. Mechanism of calcification: inhibitory role of pyrophosphate. Nature 195:911
    [Google Scholar]
  4. 4.
    Meyer JL. 1984. Can biological calcification occur in the presence of pyrophosphate?. Arch. Biochem. Biophys. 231:11–8
    [Google Scholar]
  5. 5.
    Nitschke Y, Yan Y, Buers I, Kintziger K, Askew K, Rutsch F. 2018. ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP. Exp. Mol. Med. 50:10139
    [Google Scholar]
  6. 6.
    Kato K, Nishimasu H, Oikawa D, Hirano S, Hirano H et al. 2018. Structural insights into cGAMP degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1. Nat. Commun. 9:14424
    [Google Scholar]
  7. 7.
    Carozza JA, Cordova AF, Brown JA, AlSaif Y, Bohnert V et al. 2022. ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling. PNAS 119:21e2119189119
    [Google Scholar]
  8. 8.
    Jackson EK, Dubey RK. 2001. Role of the extracellular cAMP-adenosine pathway in renal physiology. Am. J. Physiol. Renal Physiol. 281:4F597–612
    [Google Scholar]
  9. 9.
    Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M et al. 2000. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nature Genet 25:2228–31
    [Google Scholar]
  10. 10.
    Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B et al. 2001. PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. Am. J. Pathol. 158:2543–54
    [Google Scholar]
  11. 11.
    Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D et al. 2010. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am. J. Hum. Genet. 86:2273–78
    [Google Scholar]
  12. 12.
    Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. 2010. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am. J. Hum. Genet. 86:2267–72
    [Google Scholar]
  13. 13.
    Rathbun JC. 1948. Hypophosphatasia; a new developmental anomaly. Am. J. Dis. Child. 75:6822–31
    [Google Scholar]
  14. 14.
    St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C et al. 2011. NT5E mutations and arterial calcifications. New Engl. J. Med. 364:5432–42
    [Google Scholar]
  15. 15.
    Durante G. 1899. Athérome Congénital de l'aorte et de l'artère Pulmonaire. Bull. Soc. Anat. 74:97–101
    [Google Scholar]
  16. 16.
    Bryant J, White W. 1901. A case of calcification of the arteries and obliterative endarteritis, associated with hydronephrosis, in a child aged six months. Guy's Hospital Rep. 55:17–28
    [Google Scholar]
  17. 17.
    Stuart G, Wren C, Bain H. 1990. Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosphonate. Br. Heart J. 64:2156–59
    [Google Scholar]
  18. 18.
    Fleisch H, Maerki J, Russell RG. 1966. Effect of pyrophosphate on dissolution of hydroxyapatite and its possible importance in calcium homeostasis. Proc. Soc. Exp. Biol. Med. 122:2317–20
    [Google Scholar]
  19. 19.
    Fleisch H, Russell RG, Straumann F. 1966. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature 212:5065901–3
    [Google Scholar]
  20. 20.
    Meradji M, de Villeneuve VH, Huber J, de Bruijn WC, Pearse RG. 1978. Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment. J. Pediatr. 92:3401–5
    [Google Scholar]
  21. 21.
    Stuart AG. 1993. Idiopathic arterial calcification of infancy and pyrophosphate deficiency. J. Pediatr. 123:1170–71
    [Google Scholar]
  22. 22.
    Sholler GF, Yu JS, Bale PM, Hawker RE, Celermajer JM, Kozlowski K. 1984. Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival. J. Pediatr. 105:2257–60
    [Google Scholar]
  23. 23.
    Ciana G, Trappan A, Bembi B, Benettoni A, Maso G et al. 2006. Generalized arterial calcification of infancy: two siblings with prolonged survival. Eur. J. Pediatr. 165:4258–63
    [Google Scholar]
  24. 24.
    Marrott PK, Newcombe KD, Becroft DM, Friedlander DH. 1984.. Idiopathic infantile arterial calcification with survival to adult life. Pediatr. Cardiol. 5:2119–22
    [Google Scholar]
  25. 25.
    Thiaville A, Smets A, Clercx A, Perlmutter N. 1994. Idiopathic infantile arterial calcification: a surviving patient with renal artery stenosis. Pediatr. Radiol. 24:7506–8
    [Google Scholar]
  26. 26.
    Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M et al. 2012. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am. J. Hum. Genet. 90:125–39
    [Google Scholar]
  27. 27.
    Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS et al. 2020. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). Genet. Med. 23:2396–407
    [Google Scholar]
  28. 28.
    Ferreira CR, Kintzinger K, Hackbarth ME, Botschen U, Nitschke Y et al. 2021. Ectopic calcification and hypophosphatemic rickets: natural history of ENPP1 and ABCC6 deficiencies. J. Bone Miner. Res. 36:112193–202
    [Google Scholar]
  29. 29.
    Johnson K, Moffa A, Chen Y, Pritzker K, Goding J, Terkeltaub R. 1999. Matrix vesicle plasma cell membrane glycoprotein-1 regulates mineralization by murine osteoblastic MC3T3 cells. J. Bone Miner. Res. 14:6883–92
    [Google Scholar]
  30. 30.
    Hosoda Y, Yoshimura Y, Higaki S. 1981. A new breed of mouse showing multiple osteochondral lesions—twy mouse. Ryumachi 21:Suppl.157–64
    [Google Scholar]
  31. 31.
    Sakamoto M, Hosoda Y, Kojimahara K, Yamazaki T, Yoshimura Y. 1994. Arthritis and ankylosis in twy mice with hereditary multiple osteochondral lesions: with special reference to calcium deposition. Pathol. Int. 44:6420–27
    [Google Scholar]
  32. 32.
    Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. 1998. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat. Genet. 19:3271–73
    [Google Scholar]
  33. 33.
    Kobayashi Y, Goto S, Tanno T, Yamazaki M, Moriya H. 1998. Regional variations in the progression of bone loss in two different mouse osteopenia models. Calcif. Tissue Int. 62:5426–36
    [Google Scholar]
  34. 34.
    Okawa A, Goto S, Moriya H. 1999. Calcitonin simultaneously regulates both periosteal hyperostosis and trabecular osteopenia in the spinal hyperostotic mouse (twy/twy) in vivo. Calcif. Tissue Int. 64:3239–47
    [Google Scholar]
  35. 35.
    Jansen S, Perrakis A, Ulens C, Winkler C, Andries M et al. 2012. Structure of NPP1, an ectonucleotide pyrophosphatase/phosphodiesterase involved in tissue calcification. Structure 20:111948–59
    [Google Scholar]
  36. 36.
    Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T et al. 2011. Structural basis of substrate discrimination and integrin binding by autotaxin. Nat. Struct. Mol. Biol. 18:2198–204
    [Google Scholar]
  37. 37.
    Albright RA, Ornstein DL, Cao W, Chang WC, Robert D et al. 2014. Molecular basis of purinergic signal metabolism by ectonucleotide pyrophosphatase/phosphodiesterases 4 and 1 and implications in stroke. J. Biol. Chem. 289:63294–306
    [Google Scholar]
  38. 38.
    Gorelik A, Randriamihaja A, Illes K, Nagar B. 2017. A key tyrosine substitution restricts nucleotide hydrolysis by the ectoenzyme NPP5. FEBS J 284:213718–26
    [Google Scholar]
  39. 39.
    Morita J, Kano K, Kato K, Takita H, Sakagami H et al. 2016. Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase. Sci. Rep. 6:20995
    [Google Scholar]
  40. 40.
    Gorelik A, Liu F, Illes K, Nagar B. 2017. Crystal structure of the human alkaline sphingomyelinase provides insights into substrate recognition. J. Biol. Chem. 292:177087–94
    [Google Scholar]
  41. 41.
    O'Neill WC, Lomashvili KA, Malluche HH, Faugere MC, Riser BL. 2011. Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int 79:5512–17
    [Google Scholar]
  42. 42.
    Francis MD. 1969. The inhibition of calcium hydroxypatite crystal growth by polyphosphonates and polyphosphates. Calcif. Tissue Res. 3:2151–62
    [Google Scholar]
  43. 43.
    Francis MD, Russell RG, Fleisch H. 1969. Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 165:38991264–66
    [Google Scholar]
  44. 44.
    Fleisch HA, Russell RG, Bisaz S, Muhlbauer RC, Williams DA. 1970. The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur. J. Clin. Investig. 1:112–18
    [Google Scholar]
  45. 45.
    Hansen NM, Felix R, Bisaz S, Fleisch H. 1976. Aggregation of hydroxyapatite crystals. Biochim. Biophys. Acta Gen. Subj. 451:2549–59
    [Google Scholar]
  46. 46.
    Rutsch F, Boyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B et al. 2008. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ. Cardiovasc. Genet. 1:2133–40
    [Google Scholar]
  47. 47.
    Villa-Bellosta R, Sorribas V. 2013. Prevention of vascular calcification by polyphosphates and nucleotides—role of ATP. Circ. J. 77:82145–51
    [Google Scholar]
  48. 48.
    Hollwey A, Forster C, Mushtaq T. 2019. Use of disodium etidronate and sodium thiosulfate in a premature neonate with generalised arterial calcification of infancy. Arch. Dis. Child. 104:e2 (Abstr.). https://doi.org/10.1136/archdischild-2019-nppc.41
    [Crossref] [Google Scholar]
  49. 49.
    Omarjee L, Nitschke Y, Verschuere S, Bourrat E, Vignon MD et al. 2020. Severe early-onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations in ENPP1, ABCC6 and HBB: transient improvement in ectopic calcification with sodium thiosulfate. Br. J. Dermatol. 183:2367–72
    [Google Scholar]
  50. 50.
    Kingman J, Uitto J, Li Q. 2017. Elevated dietary magnesium during pregnancy and postnatal life prevents ectopic mineralization in Enpp1asj mice, a model for generalized arterial calcification of infancy. Oncotarget 8:2438152–60
    [Google Scholar]
  51. 51.
    Luo H, Li Q, Cao Y, Uitto J. 2020. Therapeutics development for pseudoxanthoma elasticum and related ectopic mineralization disorders: update 2020. J. Clin. Med. 10:1114
    [Google Scholar]
  52. 52.
    Dursun F, Atasoy Ozturk T, Guven S, Kirmizibekmez H, Seymen Karabulut G et al. 2019. Magnesium and anti-phosphate treatment with bisphosphonates for generalised arterial calcification of infancy: a case report. J. Clin. Res. Pediatr. Endocrinol. 11:3311–18
    [Google Scholar]
  53. 53.
    Otero JE, Gottesman GS, McAlister WH, Mumm S, Madson KL et al. 2013. Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J. Bone Miner. Res. 28:2419–30
    [Google Scholar]
  54. 54.
    Theng EH, Brewer CC, Oheim R, Zalewski CK, King KA et al. 2022. Characterization of hearing-impairment in generalized arterial calcification of infancy (GACI). Orphanet J. Rare Dis. 17:1273
    [Google Scholar]
  55. 55.
    Maulding ND, Kavanagh D, Zimmerman K, Coppola G, Carpenter TO et al. 2020. Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. Bone 142:115656
    [Google Scholar]
  56. 56.
    Ferreira CR, Ziegler SG, Gupta A, Groden C, Hsu KS, Gahl WA. 2016. Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification. Am. J. Med. Genet. A 170:51308–11
    [Google Scholar]
  57. 57.
    Ferreira CR, Kavanagh D, Oheim R, Zimmerman K, Sturznickel J et al. 2021. Response of the ENPP1-deficient skeletal phenotype to oral phosphate supplementation and/or enzyme replacement therapy: comparative studies in humans and mice. J. Bone Miner. Res. 36:5942–55
    [Google Scholar]
  58. 58.
    Erben RG. 2018. Physiological actions of fibroblast growth factor-23. Front. Endocrinol. 9:267
    [Google Scholar]
  59. 59.
    Stern R, Levi DS, Gales B, Rutsch F, Salusky IB. 2021. Correspondence on “Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)” by Ferreira et al. Genet. Med. 23:102006–7
    [Google Scholar]
  60. 60.
    Lomashvili KA, Garg P, Narisawa S, Millan JL, O'Neill WC 2008. Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification. Kidney Int 73:91024–30
    [Google Scholar]
  61. 61.
    Sheen CR, Kuss P, Narisawa S, Yadav MC, Nigro J et al. 2015. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification. J. Bone Miner. Res. 30:5824–36
    [Google Scholar]
  62. 62.
    Murshed M, Harmey D, Millan JL, McKee MD, Karsenty G. 2005. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev 19:91093–104
    [Google Scholar]
  63. 63.
    Shaw HM, Benjamin M. 2007. Structure-function relationships of entheses in relation to mechanical load and exercise. Scand. . J. Med. Sci. Sports 17:4303–15
    [Google Scholar]
  64. 64.
    Benjamin M, Evans EJ. 1990. Fibrocartilage. J. Anat. 171:1–15
    [Google Scholar]
  65. 65.
    Benjamin M, Ralphs JR. 1998. Fibrocartilage in tendons and ligaments—an adaptation to compressive load. J. Anat. 193:Part 4481–94
    [Google Scholar]
  66. 66.
    Benjamin M, Rufai A, Ralphs JR. 2000. The mechanism of formation of bony spurs (enthesophytes) in the Achilles tendon. Arthritis Rheum 43:3576–83
    [Google Scholar]
  67. 67.
    Hardy DC, Murphy WA, Siegel BA, Reid IR, Whyte MP. 1989. X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features. Radiology 171:2403–14
    [Google Scholar]
  68. 68.
    Reid IR, Hardy DC, Murphy WA, Teitelbaum SL, Bergfeld MA, Whyte MP. 1989. X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults. Medicine 68:6336–52
    [Google Scholar]
  69. 69.
    Chalmers J. 1993. Enthesopathy as the presenting feature of X-linked hypophosphatemia. A case report. Acta Orthop. Scand. 64:2221–23
    [Google Scholar]
  70. 70.
    Liang G, Katz LD, Insogna KL, Carpenter TO, Macica CM. 2009. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif. Tissue Int. 85:3235–46
    [Google Scholar]
  71. 71.
    Ramonda R, Sfriso P, Podswiadek M, Oliviero F, Valvason C, Punzi L. 2005. The enthesopathy of vitamin D-resistant osteomalacia in adults. Reumatismo 57:152–56
    [Google Scholar]
  72. 72.
    Karaplis AC, Bai X, Falet JP, Macica CM. 2012. Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in Hyp mice. Endocrinology 153:125906–17
    [Google Scholar]
  73. 73.
    Ferreira CR, Ansh AJ, Nester C, O'Brien C, Stabach PR et al. 2022. Musculoskeletal comorbidities and quality of life in ENPP1-deficient adults and the response of enthesopathy to enzyme replacement therapy in murine models. J. Bone Miner. Res. 37:3494–504
    [Google Scholar]
  74. 74.
    Masel JP, Cartwright DW, Latham SC. 1981. Hypophosphataemic vitamin D-resistant rickets—a cause of spinal stenosis in adults. Australas. Radiol. 25:3264–71
    [Google Scholar]
  75. 75.
    van der Kraan PM, van den Berg WB. 2007. Osteophytes: relevance and biology. Osteoarthritis Cartilage 15:3237–44
    [Google Scholar]
  76. 76.
    Rogers J, Shepstone L, Dieppe P. 2004. Is osteoarthritis a systemic disorder of bone?. Arthritis Rheum 50:2452–57
    [Google Scholar]
  77. 77.
    Gafni R, Spector E, Hartley I, Redd B, Mitnik G, Collins M. 2020. Enthesophytes are a common feature of FGF23-mediated hypophosphatemia due to tumor-induced osteomalacia. J. Endocr. Soc. 4:Suppl. 1A487 (Abstr.). http://doi.org/10.1210/jendso/bvaa046.960
    [Crossref] [Google Scholar]
  78. 78.
    Kawaguchi Y, Nakano M, Yasuda T, Seki S, Suzuki K et al. 2017. Serum biomarkers in patients with ossification of the posterior longitudinal ligament (OPLL): inflammation in OPLL. PLOS ONE 12:5e0174881
    [Google Scholar]
  79. 79.
    Kawaguchi Y, Kitajima I, Nakano M, Yasuda T, Seki S et al. 2019. Increase of the serum FGF-23 in ossification of the posterior longitudinal ligament. Global Spine J 9:5492–98
    [Google Scholar]
  80. 80.
    Mader R, Verlaan JJ, Buskila D. 2013. Diffuse idiopathic skeletal hyperostosis: clinical features and pathogenic mechanisms. Nat. Rev. Rheumatol. 9:12741–50
    [Google Scholar]
  81. 81.
    Nishimura S, Nagoshi N, Iwanami A, Takeuchi A, Hirai T et al. 2018. Prevalence and distribution of diffuse idiopathic skeletal hyperostosis on whole-spine computed tomography in patients with cervical ossification of the posterior longitudinal ligament: a multicenter study. Clin. Spine Surg. 31:9E460–65
    [Google Scholar]
  82. 82.
    Murakami Y, Mashima N, Morino T, Fukuda T, Iwase M et al. 2019. Association between vertebral fracture and diffuse idiopathic skeletal hyperostosis. Spine 44:18E1068–74
    [Google Scholar]
  83. 83.
    Park S, Lee DH, Ahn J, Cho JH, Lee SK et al. 2020. How does ossification of posterior longitudinal ligament progress in conservatively managed patients?. Spine 45:4234–43
    [Google Scholar]
  84. 84.
    Koshizuka Y, Kawaguchi H, Ogata N, Ikeda T, Mabuchi A et al. 2002. Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine. J. Bone Miner Res. 17:1138–44
    [Google Scholar]
  85. 85.
    Nakajima M, Takahashi A, Tsuji T, Karasugi T, Baba H et al. 2014. A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine. Nature Genet. 46:91012–16
    [Google Scholar]
  86. 86.
    Karasugi T, Nakajima M, Ikari KGenet. Study Group Investig. Comm. Ossification Spinal Ligaments Tsuji T et al. 2013. A genome-wide sib-pair linkage analysis of ossification of the posterior longitudinal ligament of the spine. J. Bone Miner. Metabol. 31:2136–43
    [Google Scholar]
  87. 87.
    Mader R, Pappone N, Baraliakos X, Eshed I, Sarzi-Puttini P et al. 2021. Diffuse idiopathic skeletal hyperostosis (DISH) and a possible inflammatory component. Curr. Rheumatol. Rep. 23:16
    [Google Scholar]
  88. 88.
    Chen J, Song D, Wang X, Shen X, Li Y, Yuan W. 2011. Is ossification of posterior longitudinal ligament an enthesopathy?. Int. Orthop. 35:101511–16
    [Google Scholar]
  89. 89.
    Kato H, Ansh AJ, Lester ER, Kinoshita Y, Hidaka N et al. 2022. Identification of ENPP1 haploinsufficiency in patients with diffuse idiopathic skeletal hyperostosis and early-onset osteoporosis. J. Bone Miner. Res. 37:61125–35
    [Google Scholar]
  90. 90.
    Oheim R, Zimmerman K, Maulding ND, Sturznickel J, von Kroge S et al. 2020. Human heterozygous ENPP1 deficiency is associated with early onset osteoporosis, a phenotype recapitulated in a mouse model of Enpp1 deficiency. J. Bone Miner. Res. 35:3528–39
    [Google Scholar]
  91. 91.
    Stapleton CJ, Pham MH, Attenello FJ, Hsieh PC. 2011. Ossification of the posterior longitudinal ligament: genetics and pathophysiology. Neurosurg. Focus 30:3E6
    [Google Scholar]
  92. 92.
    Epstein N. 2002. Ossification of the cervical posterior longitudinal ligament: a review. Neurosurg. Focus 13:21–10
    [Google Scholar]
  93. 93.
    Vaziri S, Lockney DT, Dru AB, Polifka AJ, Fox WC, Hoh DJ. 2019. Does ossification of the posterior longitudinal ligament progress after fusion?. Neurospine 16:3483–91
    [Google Scholar]
  94. 94.
    Chiba K, Ogawa Y, Ishii K, Takaishi H, Nakamura M et al. 2006. Long-term results of expansive open-door laminoplasty for cervical myelopathy—average 14-year follow-up study. Spine 31:262998–3005
    [Google Scholar]
  95. 95.
    Iwasaki M, Kawaguchi Y, Kimura T, Yonenobu K. 2002. Long-term results of expansive laminoplasty for ossification of the posterior longitudinal ligament of the cervical spine: more than 10 years follow up. J. Neurosurg. 96:2 Suppl.180–89
    [Google Scholar]
  96. 96.
    Kalb S, Martirosyan NL, Perez-Orribo L, Kalani MY, Theodore N. 2011. Analysis of demographics, risk factors, clinical presentation, and surgical treatment modalities for the ossified posterior longitudinal ligament. Neurosurg. Focus 30:3E11
    [Google Scholar]
  97. 97.
    Mackenzie NC, Zhu D, Milne EM, van 't Hof R, Martin A et al. 2012. Altered bone development and an increase in FGF-23 expression in Enpp1−/− mice. PLOS ONE 7:2e32177
    [Google Scholar]
  98. 98.
    Babij P, Roudier M, Graves T, Han CY, Chhoa M et al. 2009. New variants in the Enpp1 and Ptpn6 genes cause low BMD, crystal-related arthropathy, and vascular calcification. J. Bone Miner. Res. 24:91552–64
    [Google Scholar]
  99. 99.
    Anderson HC, Harmey D, Camacho NP, Garimella R, Sipe JB et al. 2005. Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleotide pyrophosphatase phosphodiesterase 1 double-deficient mice. Am. J. Pathol. 166:61711–20
    [Google Scholar]
  100. 100.
    Hajjawi MO, MacRae VE, Huesa C, Boyde A, Millan JL et al. 2014. Mineralisation of collagen rich soft tissues and osteocyte lacunae in Enpp1−/− mice. Bone 69:139–47
    [Google Scholar]
  101. 101.
    Nam HK, Liu J, Li Y, Kragor A, Hatch NE. 2011. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) protein regulates osteoblast differentiation. J. Biol. Chem. 286:4539059–71
    [Google Scholar]
  102. 102.
    Zimmerman K, Liu X, von Kroge S, Stabach P, Lester ER et al. 2022. Catalysis-independent ENPP1 protein signaling regulates mammalian bone mass. J. Bone Miner. Res. 37:91733–49
    [Google Scholar]
  103. 103.
    Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert AJ et al. 2004. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol. Endocrinol. 18:51222–37
    [Google Scholar]
  104. 104.
    Otero JE, Gottesman GS, McAlister WH, Mumm S, Madson KL et al. 2013. Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J. Bone Miner. Res. 28:2419–30
    [Google Scholar]
  105. 105.
    Li Q, Guo H, Chou DW, Berndt A, Sundberg JP, Uitto J. 2013. Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy. Dis. Model. Mech. 6:51227–35
    [Google Scholar]
  106. 106.
    Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I et al. 2015. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat. Commun. 6:10006
    [Google Scholar]
  107. 107.
    Khan T, Sinkevicius KW, Vong S, Avakian A, Leavitt MC et al. 2018. ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy (GACI). Dis. Model. Mech. 11:10035691
    [Google Scholar]
  108. 108.
    Marrott PK, Newcombe KD, Becroft DM, Friedlander DH. 1984. Idiopathic infantile arterial calcification with survival to adult life. Pediatr. Cardiol. 5:2119–22
    [Google Scholar]
  109. 109.
    Thiaville A, Smets A, Clercx A, Perlmutter N. 1994. Idiopathic infantile arterial calcification: a surviving patient with renal artery stenosis. Pediatr. Radiol. 24:7506–8
    [Google Scholar]
  110. 110.
    Stabach PR, Zimmerman K, Adame A, Kavanagh D, Saeui CT et al. 2020. Improving the pharmacodynamics and in vivo activity of ENPP1-Fc through protein and glycosylation engineering. Clin. Transl. Sci. 14:1362–72
    [Google Scholar]
  111. 111.
    Scannell JW, Blanckley A, Boldon H, Warrington B. 2012. Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug. Discov. 11:3191–200
    [Google Scholar]
  112. 112.
    Gorzelany JA, de Souza MP. 2013. Protein replacement therapies for rare diseases: a breeze for regulatory approval?. Sci. Transl. Med. 5:178178fs10
    [Google Scholar]
  113. 113.
    Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. 2014. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32:140–51
    [Google Scholar]
  114. 114.
    Ringel MS, Scannell JW, Baedeker M, Schulze U. 2020. Breaking Eroom's law. Nat. Rev. Drug Discov. 19:12833–34
    [Google Scholar]
  115. 115.
    Cheng Z, O'Brien K, Howe J, Sullivan C, Schrier D et al. 2021. INZ-701 prevents ectopic tissue calcification and restores bone architecture and growth in ENPP1-deficient mice. J. Bone Miner. Res. 36:81594–604
    [Google Scholar]
  116. 116.
    Inozyme Pharma Inc. 2023. Inozyme Pharma reports topline data from ongoing phase 1/2 trials of INZ-701.. GlobeNewswire, Feb. 16. https://www.globenewswire.com/news-release/2023/02/16/2609610/0/en/Inozyme-Pharma-Reports-Positive-Topline-Data-from-Ongoing-Phase-1-2-Trials-of-INZ-701.html
  117. 117.
    Appelman-Dijkstra NM, Papapoulos SE. 2016. From disease to treatment: from rare skeletal disorders to treatments for osteoporosis. Endocrine 52:3414–26
    [Google Scholar]
  118. 118.
    Hyder JA, Allison MA, Criqui MH, Wright CM. 2007. Association between systemic calcified atherosclerosis and bone density. Calcif. Tissue Int. 80:5301–6
    [Google Scholar]
  119. 119.
    Farhat GN, Cauley JA, Matthews KA, Newman AB, Johnston J et al. 2006. Volumetric BMD and vascular calcification in middle-aged women: the Study of Women's Health Across the Nation. J. Bone Miner. Res. 21:121839–46
    [Google Scholar]
  120. 120.
    Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. 1996. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am. J. Kidney Dis. 27:3394–401
    [Google Scholar]
  121. 121.
    Pimentel A, Urena-Torres P, Zillikens MC, Bover J, Cohen-Solal M. 2017. Fractures in patients with CKD—diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation. Kidney Int 92:61343–55
    [Google Scholar]
  122. 122.
    Lomashvili KA, Khawandi W, O'Neill WC 2005. Reduced plasma pyrophosphate levels in hemodialysis patients. J. Am. Soc. Nephrol. 16:82495–500
    [Google Scholar]
  123. 123.
    O'Neill WC, Sigrist MK, McIntyre CW. 2010. Plasma pyrophosphate and vascular calcification in chronic kidney disease. Nephrol. Dial. Transplant. 25:1187–91
    [Google Scholar]
  124. 124.
    Collab. Comput. Proj. Number 4 1994. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50:Part 5760–3
    [Google Scholar]
  125. 125.
    Rupp T, Butscheidt S, Vettorazzi E, Oheim R, Barvencik F et al. 2019. High FGF23 levels are associated with impaired trabecular bone microarchitecture in patients with osteoporosis. Osteoporos. Int. 30:81655–62
    [Google Scholar]
  126. 126.
    Carrillo-Lopez N, Panizo S, Alonso-Montes C, Roman-Garcia P, Rodriguez I et al. 2016. Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney Int 90:177–89
    [Google Scholar]
  127. 127.
    Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V et al. 2004. A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes 53:3803–11
    [Google Scholar]
  128. 128.
    Flanagan JM, Sheehan V, Linder H, Howard TA, Wang YD et al. 2013. Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia. Blood 121:163237–45
    [Google Scholar]
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