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Vascular Calcification in Uremia: New-Age Concepts about an Old-Age Problem

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Kidney Research

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1397))

Abstract

A hallmark of aging, and major contributor to the increased prevalence of cardiovascular disease in patients with chronic kidney disease (CKD), is the progressive structural and functional deterioration of the arteries and concomitant accrual of mineral. Vascular calcification (VC) was long viewed as a degenerative age-related pathology that resulted from the passive deposition of mineral in the extracellular matrix; however, since the discovery of “bone-related” protein expression in calcified atherosclerotic plaques over 20 years ago, a plethora of studies have evoked the now widely accepted view that VC is a highly regulated and principally cell-mediated phenomenon that recapitulates many features of physiologic ossification. Central to this theory are changes in vascular smooth muscle cell (VSMC) phenotype and viability, thought to be driven by chronic exposure to a number of dystrophic stimuli characteristics of the uremic state. Here, dedifferentiated synthetic VSMCs are seen to spawn calcifying matrix vesicles that actively seed mineralization of the arterial matrix. This review provides an overview of the major epidemiological, histological, and molecular aspects of VC in the context of CKD, and a counterpoint to the prevailing paradigm that emphasizes the primacy of VSMC-mediated mechanisms. Particular focus is given to the import of protein and small molecule inhibitors in regulating physiologic and pathological mineralization and the emerging role of mineral nanoparticles and their interplay with proinflammatory processes.

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References

  1. Go AS, Chertow GM, Fan D et al (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351(13):1296–1305

    Article  CAS  PubMed  Google Scholar 

  2. de Jager DJ, Grootendorst DC, Jager KJ et al (2009) Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 302(16):1782–1789

    Article  PubMed  Google Scholar 

  3. Foley RN, Parfrey PS (1998) Cardiovascular disease and mortality in ESRD. J Nephrol 11(5):239–245

    CAS  PubMed  Google Scholar 

  4. Stenvinkel P, Larsson TE (2013) Chronic kidney disease: a clinical model of premature aging. Am J Kidney Dis 62(2):339–351

    Article  PubMed  Google Scholar 

  5. Yang H, Fogo AB (2010) Cell senescence in the aging kidney. J Am Soc Nephrol 21(9):1436–1439

    Article  PubMed  Google Scholar 

  6. Lakatta EG (2013) The reality of aging viewed from the arterial wall. Artery Res 7(2):73–80

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lehto S, Niskanen L, Suhonen M et al (1996) Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 16(8):978–983

    Article  CAS  PubMed  Google Scholar 

  8. Shaw LJ, Raggi P, Berman DS et al (2006) Coronary artery calcium as a measure of biologic age. Atherosclerosis 188(1):112–119

    Article  CAS  PubMed  Google Scholar 

  9. Thompson RC, Allam AH, Lombardi GP et al (2013) Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 381(9873):1211–1222

    Article  PubMed  Google Scholar 

  10. Virchow R (1863) Cellular pathology as based upon physiological and pathological histology (trans: Frank Chance). John Churchill, London

    Google Scholar 

  11. Demer LL, Tintut Y (2008) Vascular calcification: pathobiology of a multifaceted disease. Circulation 117(22):2938–2948

    Article  PubMed  PubMed Central  Google Scholar 

  12. Monckeberg JG (1903) Über die reine Mediaverkalkung der Extremitä tenarterien und ihr Verhalten zur Arteriosklerose. Virchows Arch Pathol Anat 171:141–167

    Article  Google Scholar 

  13. Mohr W, Gorz E (2001) Granular media calcinosis of the aorta. Structural findings, historical review and pathogenetic significance. Z Kardiol 90(12):916–928

    Article  CAS  PubMed  Google Scholar 

  14. Mohr W, Gorz E (2002) Morphogenesis of media calcinosis in Monckeberg disease. Light microscopy, scanning electron microscopy and roentgen microanalysis findings. Z Kardiol 91(7):557–567

    Article  CAS  PubMed  Google Scholar 

  15. Klotz O (1905) Studies upon calcareous degeneration: I. The process of pathological calcification. J Exp Med 7(6):633–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Silbert S, Lippmann HI, Gordon E (1953) Monckeberg’s arteriosclerosis. J Am Med Assoc 151(14):1176–1179

    Article  CAS  PubMed  Google Scholar 

  17. Elliott RJ, McGrath LT (1994) Calcification of the human thoracic aorta during aging. Calcif Tissue Int 54(4):268–273

    Article  CAS  PubMed  Google Scholar 

  18. Janzen J, Vuong PN (2001) Arterial calcifications: morphological aspects and their pathological implications. Z Kardiol 90(Suppl 3):6–11

    PubMed  Google Scholar 

  19. Schlieper G, Aretz A, Verberckmoes SC et al (2010) Ultrastructural analysis of vascular calcifications in uremia. J Am Soc Nephrol 21(4):689–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Verberckmoes SC, Persy V, Behets GJ et al (2007) Uremia-related vascular calcification: more than apatite deposition. Kidney Int 71(4):298–303

    Article  CAS  PubMed  Google Scholar 

  21. Schmermund A, Mohlenkamp S, Erbel R (2003) Coronary artery calcium and its relationship to coronary artery disease. Cardiol Clin 21(4):521–534

    Article  PubMed  Google Scholar 

  22. Drueke TB, Massy ZA (2010) Atherosclerosis in CKD: differences from the general population. Nat Rev Nephrol 6(12):723–735

    Article  PubMed  Google Scholar 

  23. Vengrenyuk Y, Carlier S, Xanthos S et al (2006) A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci U S A 103(40):14678–14683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin TC, Tintut Y, Lyman A et al (2006) Mechanical response of a calcified plaque model to fluid shear force. Ann Biomed Eng 34(10):1535–1541

    Article  PubMed  Google Scholar 

  25. Aikawa M, Libby P (2004) The vulnerable atherosclerotic plaque: pathogenesis and therapeutic approach. Cardiovasc Pathol 13(3):125–138

    Article  PubMed  Google Scholar 

  26. London GM, Pannier B, Marchais SJ (2013) Vascular calcifications, arterial aging and arterial remodeling in ESRD. Blood Purif 35(1-3):16–21

    Article  CAS  PubMed  Google Scholar 

  27. Mitchell GF (2008) Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol (1985) 105(5):1652–1660

    Article  Google Scholar 

  28. Lanzer P, Boehm M, Sorribas V et al (2014) Medial vascular calcification revisited: review and perspectives. Eur Heart J 35(23):1515–1525

    Article  PubMed  PubMed Central  Google Scholar 

  29. Goodman WG, Goldin J, Kuizon BD et al (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342(20):1478–1483

    Article  CAS  PubMed  Google Scholar 

  30. Longenecker JC, Coresh J, Powe NR et al (2002) Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol 13(7):1918–1927

    Article  PubMed  Google Scholar 

  31. Wanner C, Krane V, Marz W et al (2005) Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353(3):238–248

    Article  CAS  PubMed  Google Scholar 

  32. Ritz E, Strumpf C, Katz F et al (1985) Hypertension and cardiovascular risk factors in hemodialyzed diabetic patients. Hypertension 7(6 Pt 2):II118–II124

    CAS  PubMed  Google Scholar 

  33. Parfrey PS, Foley RN, Harnett JD et al (1996) Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int 49(5):1428–1434

    Article  CAS  PubMed  Google Scholar 

  34. Weiner DE, Tabatabai S, Tighiouart H et al (2006) Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis 48(3):392–401

    Article  PubMed  Google Scholar 

  35. Meisinger C, Doring A, Lowel H et al (2006) Chronic kidney disease and risk of incident myocardial infarction and all-cause and cardiovascular disease mortality in middle-aged men and women from the general population. Eur Heart J 27(10):1245–1250

    Article  PubMed  Google Scholar 

  36. Parfrey PS (2000) Cardiac disease in dialysis patients: diagnosis, burden of disease, prognosis, risk factors and management. Nephrol Dial Transplant 15(Suppl 5):58–68

    Article  PubMed  Google Scholar 

  37. Middleton RJ, Parfrey PS, Foley RN (2001) Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol 12(5):1079–1084

    CAS  PubMed  Google Scholar 

  38. Lau WL, Ix JH (2013) Clinical detection, risk factors, and cardiovascular consequences of medial arterial calcification: a pattern of vascular injury associated with aberrant mineral metabolism. Semin Nephrol 33(2):93–105

    Article  CAS  PubMed  Google Scholar 

  39. Shroff RC, McNair R, Figg N et al (2008) Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation 118(17):1748–1757

    Article  CAS  PubMed  Google Scholar 

  40. Raggi P, Boulay A, Chasan-Taber S et al (2002) Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 39(4):695–701

    Article  PubMed  Google Scholar 

  41. Smith E, Slater R (1972) Relationship between low-density lipoprotein in aortic intima and serum-lipid levels. Lancet 299(7748):463–469

    Article  Google Scholar 

  42. Moe SM, O’Neill KD, Fineberg N et al (2003) Assessment of vascular calcification in ESRD patients using spiral CT. Nephrol Dial Transplant 18(6):1152–1158

    Article  CAS  PubMed  Google Scholar 

  43. London GM, Marchais SJ, Guerin AP et al (2008) Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD. J Am Soc Nephrol 19(9):1827–1835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rennenberg RJ, Kessels AG, Schurgers LJ et al (2009) Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis. Vasc Health Risk Manag 5(1):185–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Raggi P, Bellasi A, Ferramosca E et al (2007) Pulse wave velocity is inversely related to vertebral bone density in hemodialysis patients. Hypertension 49(6):1278–1284

    Article  CAS  PubMed  Google Scholar 

  46. Toussaint ND, Lau KK, Strauss BJ et al (2010) Effect of alendronate on vascular calcification in CKD stages 3 and 4: a pilot randomized controlled trial. Am J Kidney Dis 56(1):57–68

    Article  CAS  PubMed  Google Scholar 

  47. Bucay N, Sarosi I, Dunstan CR et al (1998) osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12(9):1260–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. D’Amelio P, Isaia G, Isaia GC (2009) The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. J Endocrinol Invest 32(4 Suppl):6–9

    PubMed  Google Scholar 

  49. Kuro-o M, Matsumura Y, Aizawa H et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390(6655):45–51

    Article  CAS  PubMed  Google Scholar 

  50. Boyd W (1932) A text-book of pathology, 1st edn. Lea & Febiger, Philadelphia

    Google Scholar 

  51. Vyavahare N, Ogle M, Schoen FJ et al (1999) Elastin calcification and its prevention with aluminum chloride pretreatment. Am J Pathol 155(3):973–982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bostrom K, Watson KE, Horn S et al (1993) Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 91(4):1800–1809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sallam T, Cheng H, Demer LL et al (2013) Regulatory circuits controlling vascular cell calcification. Cell Mol Life Sci 70(17):3187–3197

    Article  CAS  PubMed  Google Scholar 

  54. Sage AP, Tintut Y, Demer LL (2010) Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 7(9):528–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shroff RC, McNair R, Skepper JN et al (2010) Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J Am Soc Nephrol 21(1):103–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shanahan CM, Cary NR, Salisbury JR et al (1999) Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 100(21):2168–2176

    Article  CAS  PubMed  Google Scholar 

  57. Proudfoot D, Skepper JN, Hegyi L et al (2000) Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 87(11):1055–1062

    Article  CAS  PubMed  Google Scholar 

  58. Yao Y, Jumabay M, Ly A et al (2013) A role for the endothelium in vascular calcification. Circ Res 113(5):495–504

    Article  CAS  PubMed  Google Scholar 

  59. Qiu H, Zhu Y, Sun Z et al (2010) Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res 107(5):615–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gomez D, Owens GK (2012) Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res 95(2):156–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tyson KL, Reynolds JL, McNair R et al (2003) Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol 23(3):489–494

    Article  CAS  PubMed  Google Scholar 

  62. Bostrom KI, Rajamannan NM, Towler DA (2011) The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res 109(5):564–577

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Kapustin AN, Davies JD, Reynolds JL et al (2011) Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ Res 109(1):e1–e12

    Article  CAS  PubMed  Google Scholar 

  64. Byon CH, Javed A, Dai Q et al (2008) Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J Biol Chem 283(22):15319–15327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jono S, McKee MD, Murry CE et al (2000) Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 87(7):E10–E17

    Article  CAS  PubMed  Google Scholar 

  66. Speer MY, Li X, Hiremath PG et al (2010) Runx2/Cbfa1, but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis. J Cell Biochem 110(4):935–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sun Y, Byon CH, Yuan K et al (2012) Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res 111(5):543–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sage AP, Lu J, Tintut Y et al (2011) Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney Int 79(4):414–422

    Article  CAS  PubMed  Google Scholar 

  69. Li X, Yang HY, Giachelli CM (2006) Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res 98(7):905–912

    Article  CAS  PubMed  Google Scholar 

  70. Crouthamel MH, Lau WL, Leaf EM et al (2013) Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arterioscler Thromb Vasc Biol 33(11):2625–2632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nguyen AT, Gomez D, Bell RD et al (2013) Smooth muscle cell plasticity: fact or fiction? Circ Res 112(1):17–22

    Article  CAS  PubMed  Google Scholar 

  72. Liu Y, Shanahan CM (2011) Signalling pathways and vascular calcification. Front Biosci 16:1302–1314

    Article  CAS  Google Scholar 

  73. Shanahan CM, Weissberg PL, Metcalfe JC (1993) Isolation of gene markers of differentiated and proliferating vascular smooth muscle cells. Circ Res 73(1):193–204

    Article  CAS  PubMed  Google Scholar 

  74. Gittenberger-de Groot AC, DeRuiter MC, Bergwerff M et al (1999) Smooth muscle cell origin and its relation to heterogeneity in development and disease. Arterioscler Thromb Vasc Biol 19(7):1589–1594

    Article  CAS  PubMed  Google Scholar 

  75. Proudfoot D, Shanahan C (2012) Human vascular smooth muscle cell culture. Methods Mol Biol 806:251–263

    Article  CAS  PubMed  Google Scholar 

  76. Proudfoot D, Skepper JN, Shanahan CM et al (1998) Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol 18(3):379–388

    Article  CAS  PubMed  Google Scholar 

  77. Lomashvili KA, O’Neill WC (2009) On vascular calcification prevention with phosphonoformate and bisphosphonates. Kidney Int 75(12):1356

    Article  Google Scholar 

  78. Al-Aly Z, Shao JS, Lai CF et al (2007) Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr-/- mice. Arterioscler Thromb Vasc Biol 27(12):2589–2596

    Article  CAS  PubMed  Google Scholar 

  79. Neven E, Dauwe S, De Broe ME et al (2007) Endochondral bone formation is involved in media calcification in rats and in men. Kidney Int 72(5):574–581

    Article  CAS  PubMed  Google Scholar 

  80. El-Abbadi MM, Pai AS, Leaf EM et al (2009) Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. Kidney Int 75(12):1297–1307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Davies MR, Lund RJ, Hruska KA (2003) BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol 14(6):1559–1567

    Article  PubMed  Google Scholar 

  82. Luo G, Ducy P, McKee MD et al (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386(6620):78–81

    Article  CAS  PubMed  Google Scholar 

  83. Speer MY, Yang HY, Brabb T et al (2009) Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res 104(6):733–741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jahnen-Dechent W, Heiss A, Schafer C et al (2011) Fetuin-A regulation of calcified matrix metabolism. Circ Res 108(12):1494–1509

    Article  CAS  PubMed  Google Scholar 

  85. Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84(3):767–801

    Article  CAS  PubMed  Google Scholar 

  86. Li L, Miano JM, Cserjesi P et al (1996) SM22 alpha, a marker of adult smooth muscle, is expressed in multiple myogenic lineages during embryogenesis. Circ Res 78(2):188–195

    Article  CAS  PubMed  Google Scholar 

  87. Stewart HJ, Guildford AL, Lawrence-Watt DJ et al (2009) Substrate-induced phenotypical change of monocytes/macrophages into myofibroblast-like cells: a new insight into the mechanism of in-stent restenosis. J Biomed Mater Res A 90(2):465–471

    Article  CAS  PubMed  Google Scholar 

  88. Martin K, Weiss S, Metharom P et al (2009) Thrombin stimulates smooth muscle cell differentiation from peripheral blood mononuclear cells via protease-activated receptor-1, RhoA, and myocardin. Circ Res 105(3):214–218

    Article  CAS  PubMed  Google Scholar 

  89. Rong JX, Shapiro M, Trogan E et al (2003) Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci U S A 100(23):13531–13536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. O’Brien ER, Garvin MR, Stewart DK et al (1994) Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb 14(10):1648–1656

    Article  PubMed  Google Scholar 

  91. Shanahan CM, Cary NR, Metcalfe JC et al (1994) High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest 93(6):2393–2402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wallin R, Cain D, Sane DC (1999) Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells--a cell system which resembles the system in bone cells. Thromb Haemost 82(6):1764–1767

    CAS  PubMed  Google Scholar 

  93. Yoshida H, Yokoyama K, Yaginuma T et al (2011) Difference in coronary artery intima and media calcification in autopsied patients with chronic kidney disease. Clin Nephrol 75(1):1–7

    CAS  PubMed  Google Scholar 

  94. O’Neill WC, Adams AL (2013) Breast arterial calcification in chronic kidney disease: absence of smooth muscle apoptosis and osteogenic transdifferentiation. Kidney Int 85(3):668–676

    Article  PubMed  CAS  Google Scholar 

  95. Moe SM, O’Neill KD, Duan D et al (2002) Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 61(2):638–647

    Article  PubMed  Google Scholar 

  96. Gross ML, Meyer HP, Ziebart H et al (2007) Calcification of coronary intima and media: immunohistochemistry, backscatter imaging, and x-ray analysis in renal and nonrenal patients. Clin J Am Soc Nephrol 2(1):121–134

    Article  PubMed  Google Scholar 

  97. Fang Y, Ginsberg C, Sugatani T et al (2014) Early chronic kidney disease-mineral bone disorder stimulates vascular calcification. Kidney Int 85(1):142–150

    Article  CAS  PubMed  Google Scholar 

  98. Pai A, Leaf EM, El-Abbadi M et al (2011) Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. Am J Pathol 178(2):764–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mathew S, Tustison KS, Sugatani T et al (2008) The mechanism of phosphorus as a cardiovascular risk factor in CKD. J Am Soc Nephrol 19(6):1092–1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Keutel J, Jorgensen G, Gabriel P (1971) A new autosomal-recessive hereditary syndrome. Multiple peripheral pulmonary stenosis, brachytelephalangia, inner-ear deafness, ossification or calcification of cartilages. Dtsch Med Wochenschr 96(43):1676–1681, passim

    Article  CAS  PubMed  Google Scholar 

  101. Rutsch F, Ruf N, Vaingankar S et al (2003) Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34(4):379–381

    Article  CAS  PubMed  Google Scholar 

  102. Okawa A, Nakamura I, Goto S et al (1998) Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet 19(3):271–273

    Article  CAS  PubMed  Google Scholar 

  103. Sakamoto M, Hosoda Y, Kojimahara K et al (1994) Arthritis and ankylosis in twy mice with hereditary multiple osteochondral lesions: with special reference to calcium deposition. Pathol Int 44(6):420–427

    Article  CAS  PubMed  Google Scholar 

  104. Jahnen-Dechent W, Schafer C, Ketteler M et al (2008) Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification. J Mol Med 86(4):379–389

    Article  CAS  PubMed  Google Scholar 

  105. Khavandgar Z, Roman H, Li J et al (2014) Elastin haploinsufficiency impedes the progression of arterial calcification in MGP-deficient mice. J Bone Miner Res 29(2):327–337

    Article  CAS  PubMed  Google Scholar 

  106. Ghadially FN, Meachim G, Collins DH (1965) Extra-cellular lipid in the matrix of human articular cartilage. Ann Rheum Dis 24:136–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Holtrop ME (1972) The ultrastructure of the epiphyseal plate. II The hypertrophic chondrocyte. Calcif Tissue Res 9(2):140–151

    Article  CAS  PubMed  Google Scholar 

  108. Anderson HC (1967) Electron microscopic studies of induced cartilage development and calcification. J Cell Biol 35(1):81–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bonucci E (1967) Fine structure of early cartilage calcification. J Ultrastruct Res 20(1):33–50

    Article  CAS  PubMed  Google Scholar 

  110. Anderson HC (2003) Matrix vesicles and calcification. Curr Rheumatol Rep 5(3):222–226

    Article  PubMed  Google Scholar 

  111. van der Pol E, Boing AN, Harrison P et al (2012) Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 64(3):676–705

    Article  PubMed  CAS  Google Scholar 

  112. Genge BR, Wu LN, Wuthier RE (1989) Identification of phospholipid-dependent calcium-binding proteins as constituents of matrix vesicles. J Biol Chem 264(18):10917–10921

    CAS  PubMed  Google Scholar 

  113. Anderson HC, Sipe JB, Hessle L et al (2004) Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase-deficient mice. Am J Pathol 164(3):841–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Reynolds JL, Joannides AJ, Skepper JN et al (2004) Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 15(11):2857–2867

    Article  CAS  PubMed  Google Scholar 

  115. Anderson HC (1988) Mechanisms of pathologic calcification. Rheum Dis Clin North Am 14(2):303–319

    CAS  PubMed  Google Scholar 

  116. Wu LN, Genge BR, Wuthier RE (1991) Association between proteoglycans and matrix vesicles in the extracellular matrix of growth plate cartilage. J Biol Chem 266(2):1187–1194

    CAS  PubMed  Google Scholar 

  117. Felix R, Fleisch H (1976) The role of matrix vesicles in calcification. Calcif Tissue Res 21(Suppl):344–348

    PubMed  Google Scholar 

  118. Ghadially FN (2001) As you like it, part 3: a critique and historical review of calcification as seen with the electron microscope. Ultrastruct Pathol 25(3):243–267

    Article  CAS  PubMed  Google Scholar 

  119. New SE, Goettsch C, Aikawa M et al (2013) Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res 113(1):72–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kim KM (1976) Calcification of matrix vesicles in human aortic valve and aortic media. Fed Proc 35(2):156–162

    CAS  PubMed  Google Scholar 

  121. Kumata C, Mizobuchi M, Ogata H et al (2011) Involvement of matrix metalloproteinase-2 in the development of medial layer vascular calcification in uremic rats. Ther Apher Dial 15(Suppl 1):18–22

    Article  CAS  PubMed  Google Scholar 

  122. Shanahan CM, Crouthamel MH, Kapustin A et al (2011) Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res 109(6):697–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. De Yoreo JJ, Vekilov PG (2003) Principles of crystal nucleation and growth. Rev Mineral Geochem 54(1):57–93

    Article  Google Scholar 

  124. Wang L, Nancollas GH (2008) Calcium orthophosphates: crystallization and dissolution. Chem Rev 108(11):4628–4669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gersh I (1938) The fate of colloidal calcium phosphate in the dog. Am J Physiol 121(3):589–594

    CAS  Google Scholar 

  126. Gersh I (1938) Histochemical studies on the fate of colloidal calcium phosphate in the rat. Anat Rec 70(3):331–349

    Article  CAS  Google Scholar 

  127. McLean FC, Hinrichs MA (1938) The formation and behavior of colloidal calcium phosphate in the blood. Am J Physiol 121(3):580–588

    CAS  Google Scholar 

  128. Ho AM, Johnson MD, Kingsley DM (2000) Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289(5477):265–270

    Article  CAS  PubMed  Google Scholar 

  129. Rutsch F, Vaingankar S, Johnson K et al (2001) PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. Am J Pathol 158(2):543–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kirsch T (2012) Biomineralization--an active or passive process? Connect Tissue Res 53(6):438–445

    Article  CAS  PubMed  Google Scholar 

  131. Murshed M, Harmey D, Millan JL et al (2005) Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev 19(9):1093–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Murshed M, McKee MD (2010) Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr Opin Nephrol Hypertens 19(4):359–365

    Article  CAS  PubMed  Google Scholar 

  133. Prosdocimo DA, Wyler SC, Romani AM et al (2010) Regulation of vascular smooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia. Am J Physiol Cell Physiol 298(3):C702–C713

    Article  CAS  PubMed  Google Scholar 

  134. Reynolds JL, Skepper JN, McNair R et al (2005) Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol 16(10):2920–2930

    Article  CAS  PubMed  Google Scholar 

  135. Wallin R, Schurgers LJ, Loeser RF (2010) Biosynthesis of the vitamin K-dependent matrix Gla protein (MGP) in chondrocytes: a fetuin-MGP protein complex is assembled in vesicles shed from normal but not from osteoarthritic chondrocytes. Osteoarthritis Cartilage 18(8):1096–1103

    Article  CAS  PubMed  Google Scholar 

  136. Schafer C, Heiss A, Schwarz A et al (2003) The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 112(3):357–366

    Article  PubMed  PubMed Central  Google Scholar 

  137. Yao Y, Bennett BJ, Wang X et al (2010) Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification. Circ Res 107(4):485–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zebboudj AF, Shin V, Bostrom K (2003) Matrix GLA protein and BMP-2 regulate osteoinduction in calcifying vascular cells. J Cell Biochem 90(4):756–765

    Article  CAS  PubMed  Google Scholar 

  139. Schurgers LJ, Cranenburg EC, Vermeer C (2008) Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 100(4):593–603

    CAS  PubMed  Google Scholar 

  140. Schurgers LJ, Uitto J, Reutelingsperger CP (2013) Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med 19(4):217–226

    Article  CAS  PubMed  Google Scholar 

  141. Villa-Bellosta R, Sorribas V (2011) Calcium phosphate deposition with normal phosphate concentration. -Role of pyrophosphate. Circ J 75(11):2705–2710

    Article  CAS  PubMed  Google Scholar 

  142. O’Neill WC (2006) Pyrophosphate, alkaline phosphatase, and vascular calcification. Circ Res 99(2), e2

    Article  PubMed  Google Scholar 

  143. Schoppet M, Shanahan CM (2008) Role for alkaline phosphatase as an inducer of vascular calcification in renal failure? Kidney Int 73(9):989–991

    Article  CAS  PubMed  Google Scholar 

  144. Lomashvili KA, Garg P, Narisawa S et al (2008) Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification. Kidney Int 73(9):1024–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Price PA, Toroian D, Chan WS (2009) Tissue-nonspecific alkaline phosphatase is required for the calcification of collagen in serum: a possible mechanism for biomineralization. J Biol Chem 284(7):4594–4604

    Article  CAS  PubMed  Google Scholar 

  146. Prosdocimo DA, Douglas DC, Romani AM et al (2009) Autocrine ATP release coupled to extracellular pyrophosphate accumulation in vascular smooth muscle cells. Am J Physiol Cell Physiol 296(4):C828–C839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Block GA (2000) Prevalence and clinical consequences of elevated Ca x P product in hemodialysis patients. Clin Nephrol 54(4):318–324

    CAS  PubMed  Google Scholar 

  148. Block GA, Klassen PS, Lazarus JM et al (2004) Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15(8):2208–2218

    Article  CAS  PubMed  Google Scholar 

  149. Shroff R (2013) Phosphate is a vascular toxin. Pediatr Nephrol 28(4):583–593

    Article  PubMed  Google Scholar 

  150. Giachelli CM (2009) The emerging role of phosphate in vascular calcification. Kidney Int 75(9):890–897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Lau WL, Pai A, Moe SM et al (2011) Direct effects of phosphate on vascular cell function. Adv Chronic Kidney Dis 18(2):105–112

    Article  PubMed  PubMed Central  Google Scholar 

  152. Ketteler M, Wolf M, Hahn K et al (2013) Phosphate: a novel cardiovascular risk factor. Eur Heart J 34(15):1099–1101

    Article  PubMed  Google Scholar 

  153. Hruska K, Mathew S, Lund R et al (2011) Cardiovascular risk factors in chronic kidney disease: does phosphate qualify? Kidney Int Suppl 121:S9–S13

    Article  CAS  Google Scholar 

  154. Di Marco GS, Hausberg M, Hillebrand U et al (2008) Increased inorganic phosphate induces human endothelial cell apoptosis in vitro. Am J Physiol Renal Physiol 294(6):F1381–F1387

    Article  PubMed  CAS  Google Scholar 

  155. Ewence AE, Bootman M, Roderick HL et al (2008) Calcium phosphate crystals induce cell death in human vascular smooth muscle cells: a potential mechanism in atherosclerotic plaque destabilization. Circ Res 103(5):e28–e34

    Article  CAS  PubMed  Google Scholar 

  156. Villa-Bellosta R, Sorribas V (2009) Phosphonoformic acid prevents vascular smooth muscle cell calcification by inhibiting calcium-phosphate deposition. Arterioscler Thromb Vasc Biol 29(5):761–766

    Article  CAS  PubMed  Google Scholar 

  157. Villa-Bellosta R, Millan A, Sorribas V (2011) Role of calcium-phosphate deposition in vascular smooth muscle cell calcification. Am J Physiol Cell Physiol 300(1):C210–C220

    Article  CAS  PubMed  Google Scholar 

  158. Khoshniat S, Bourgine A, Julien M et al (2011) Phosphate-dependent stimulation of MGP and OPN expression in osteoblasts via the ERK1/2 pathway is modulated by calcium. Bone 48(4):894–902

    Article  CAS  PubMed  Google Scholar 

  159. Jin C, Frayssinet P, Pelker R et al (2011) NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy. Proc Natl Acad Sci U S A 108(36):14867–14872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pazar B, Ea HK, Narayan S et al (2011) Basic calcium phosphate crystals induce monocyte/macrophage IL-1beta secretion through the NLRP3 inflammasome in vitro. J Immunol 186(4):2495–2502

    Article  CAS  PubMed  Google Scholar 

  161. Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13(6):397–411

    Article  CAS  PubMed  Google Scholar 

  162. Robbins GR, Wen H, Ting JP (2014) Inflammasomes and metabolic disorders: old genes in modern diseases. Mol Cell 54(2):297–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ea HK, Liote F (2009) Advances in understanding calcium-containing crystal disease. Curr Opin Rheumatol 21(2):150–157

    Article  CAS  PubMed  Google Scholar 

  164. McCarthy GM (2009) Inspirational calcification: how rheumatology research directs investigation in vascular biology. Curr Opin Rheumatol 21(1):47–49

    Article  PubMed  Google Scholar 

  165. Halverson PB, Greene A, Cheung HS (1998) Intracellular calcium responses to basic calcium phosphate crystals in fibroblasts. Osteoarthritis Cartilage 6(5):324–329

    Article  CAS  PubMed  Google Scholar 

  166. McCarthy GM, Augustine JA, Baldwin AS et al (1998) Molecular mechanism of basic calcium phosphate crystal-induced activation of human fibroblasts. Role of nuclear factor kappab, activator protein 1, and protein kinase c. J Biol Chem 273(52):35161–35169

    Article  CAS  PubMed  Google Scholar 

  167. Jiang W, Kim BY, Rutka JT et al (2008) Nanoparticle-mediated cellular response is size-dependent. Nat Nanotechnol 3(3):145–150

    Article  CAS  PubMed  Google Scholar 

  168. Schmid K, McSharry WO, Pameijer CH et al (1980) Chemical and physicochemical studies on the mineral deposits of the human atherosclerotic aorta. Atherosclerosis 37(2):199–210

    Article  CAS  PubMed  Google Scholar 

  169. Nadra I, Boccaccini AR, Philippidis P et al (2008) Effect of particle size on hydroxyapatite crystal-induced tumor necrosis factor alpha secretion by macrophages. Atherosclerosis 196(1):98–105

    Article  CAS  PubMed  Google Scholar 

  170. Laquerriere P, Grandjean-Laquerriere A, Jallot E et al (2003) Importance of hydroxyapatite particles characteristics on cytokines production by human monocytes in vitro. Biomaterials 24(16):2739–2747

    Article  CAS  PubMed  Google Scholar 

  171. Hornung V, Bauernfeind F, Halle A et al (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9(8):847–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Duewell P, Kono H, Rayner KJ et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Peng HH, Wu CY, Young D et al (2013) Physicochemical and biological properties of biomimetic mineralo-protein nanoparticles formed spontaneously in biological fluids. Small 9(13):2297–2307

    Article  CAS  PubMed  Google Scholar 

  174. Kim HJ, Delaney JD, Kirsch T (2010) The role of pyrophosphate/phosphate homeostasis in terminal differentiation and apoptosis of growth plate chondrocytes. Bone 47(3):657–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Simionescu A, Philips K, Vyavahare N (2005) Elastin-derived peptides and TGF-beta1 induce osteogenic responses in smooth muscle cells. Biochem Biophys Res Commun 334(2):524–532

    Article  CAS  PubMed  Google Scholar 

  176. Franceschi C, Bonafe M, Valensin S et al (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    Article  CAS  PubMed  Google Scholar 

  177. Collerton J, Martin-Ruiz C, Davies K et al (2012) Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study. Mech Ageing Dev 133(6):456–466

    Article  CAS  PubMed  Google Scholar 

  178. Schumacher W, Cockcroft J, Timpson NJ et al (2009) Association between C-reactive protein genotype, circulating levels, and aortic pulse wave velocity. Hypertension 53(2):150–157

    Article  CAS  PubMed  Google Scholar 

  179. Lilitkarntakul P, Dhaun N, Melville V et al (2011) Blood pressure and not uraemia is the major determinant of arterial stiffness and endothelial dysfunction in patients with chronic kidney disease and minimal co-morbidity. Atherosclerosis 216(1):217–225

    Article  CAS  PubMed  Google Scholar 

  180. Zanoli L, Cannavo M, Rastelli S et al (2012) Arterial stiffness is increased in patients with inflammatory bowel disease. J Hypertens 30(9):1775–1781

    Article  CAS  PubMed  Google Scholar 

  181. Wallberg-Jonsson S, Caidahl K, Klintland N et al (2008) Increased arterial stiffness and indication of endothelial dysfunction in long-standing rheumatoid arthritis. Scand J Rheumatol 37(1):1–5

    Article  CAS  PubMed  Google Scholar 

  182. Pieringer H, Schumacher S, Stuby U et al (2009) Augmentation index and large-artery remodeling in patients with longstanding rheumatoid arthritis compared with healthy controls. Semin Arthritis Rheum 39(3):163–169

    Article  PubMed  Google Scholar 

  183. Pieringer H, Pichler M (2011) Cardiovascular morbidity and mortality in patients with rheumatoid arthritis: vascular alterations and possible clinical implications. QJM 104(1):13–26

    Article  CAS  PubMed  Google Scholar 

  184. Greene ER, Lanphere KR, Sharrar J et al (2009) Arterial distensibility in systemic lupus erythematosus. Conf Proc IEEE Eng Med Biol Soc 2009:1109–1112

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Maki-Petaja KM, Elkhawad M, Cheriyan J et al (2012) Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation 126(21):2473–2480

    Article  PubMed  CAS  Google Scholar 

  186. Wang S, Yiu KH, Mok MY et al (2009) Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis. J Intern Med 266(5):445–452

    Article  CAS  PubMed  Google Scholar 

  187. Yiu KH, Wang S, Mok MY et al (2011) Relationship between cardiac valvular and arterial calcification in patients with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 38(4):621–627

    Article  PubMed  Google Scholar 

  188. Molad Y, Levin-Iaina N, Vaturi M et al (2006) Heart valve calcification in young patients with systemic lupus erythematosus: a window to premature atherosclerotic vascular morbidity and a risk factor for all-cause mortality. Atherosclerosis 185(2):406–412

    Article  CAS  PubMed  Google Scholar 

  189. Sato H, Kazama JJ, Wada Y et al (2007) Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A (AHSG) in patients with rheumatoid arthritis. Intern Med 46(20):1685–1691

    Article  PubMed  Google Scholar 

  190. Marhaug G, Shah V, Shroff R et al (2008) Age-dependent inhibition of ectopic calcification: a possible role for fetuin-A and osteopontin in patients with juvenile dermatomyositis with calcinosis. Rheumatology 47(7):1031–1037

    Article  CAS  PubMed  Google Scholar 

  191. Stenvinkel P, Ketteler M, Johnson RJ et al (2005) IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly. Kidney Int 67(4):1216–1233

    Article  CAS  PubMed  Google Scholar 

  192. Carrero JJ, Stenvinkel P, Fellstrom B et al (2008) Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients. J Intern Med 263(3):302–312

    Article  CAS  PubMed  Google Scholar 

  193. Ramirez R, Carracedo J, Soriano S et al (2005) Stress-induced premature senescence in mononuclear cells from patients on long-term hemodialysis. Am J Kidney Dis 45(2):353–359

    Article  PubMed  Google Scholar 

  194. Seidler S, Zimmermann HW, Bartneck M et al (2010) Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol 11:30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Noh H, Yu MR, Kim HJ et al (2012) Uremia induces functional incompetence of bone marrow-derived stromal cells. Nephrol Dial Transplant 27(1):218–225

    Article  CAS  PubMed  Google Scholar 

  196. Ramirez R, Carracedo J, Merino A et al (2011) CD14+CD16+ monocytes from chronic kidney disease patients exhibit increased adhesion ability to endothelial cells. Contrib Nephrol 171:57–61

    Article  CAS  PubMed  Google Scholar 

  197. Andrews NP, Fujii H, Goronzy JJ et al (2010) Telomeres and immunological diseases of aging. Gerontology 56(4):390–403

    Article  CAS  PubMed  Google Scholar 

  198. Rodier F, Coppe JP, Patil CK et al (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11(8):973–979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Tintut Y, Patel J, Parhami F et al (2000) Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 102(21):2636–2642

    Article  CAS  PubMed  Google Scholar 

  200. Son BK, Akishita M, Iijima K et al (2008) Adiponectin antagonizes stimulatory effect of tumor necrosis factor-alpha on vascular smooth muscle cell calcification: regulation of growth arrest-specific gene 6-mediated survival pathway by adenosine 5′-monophosphate-activated protein kinase. Endocrinology 149(4):1646–1653

    Article  CAS  PubMed  Google Scholar 

  201. Abedin M, Lim J, Tang TB et al (2006) N-3 fatty acids inhibit vascular calcification via the p38-mitogen-activated protein kinase and peroxisome proliferator-activated receptor-gamma pathways. Circ Res 98(6):727–729

    Article  CAS  PubMed  Google Scholar 

  202. Awan Z, Denis M, Roubtsova A et al. (2015) Reducing vascular calcification by anti-IL-1beta monoclonal antibody in a mouse model of familial hypercholesterolemia. Angiology doi: 10.1177/0003319715583205

    Google Scholar 

  203. Aikawa E, Nahrendorf M, Figueiredo JL et al (2007) Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 116(24):2841–2850

    Article  CAS  PubMed  Google Scholar 

  204. Hjortnaes J, Butcher J, Figueiredo JL et al (2010) Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur Heart J 31(16):1975–1984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Abdelbaky A, Corsini E, Figueroa AL et al (2013) Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study. Circ Cardiovasc Imaging 6(5):747–754

    Article  PubMed  Google Scholar 

  206. Tanikawa T, Okada Y, Tanikawa R et al (2009) Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J Vasc Res 46(6):572–580

    Article  CAS  PubMed  Google Scholar 

  207. Bear M, Butcher M, Shaughnessy SG (2008) Oxidized low-density lipoprotein acts synergistically with beta-glycerophosphate to induce osteoblast differentiation in primary cultures of vascular smooth muscle cells. J Cell Biochem 105(1):185–193

    Article  CAS  PubMed  Google Scholar 

  208. Goettsch C, Rauner M, Hamann C et al (2011) Nuclear factor of activated T cells mediates oxidised LDL-induced calcification of vascular smooth muscle cells. Diabetologia 54(10):2690–2701

    Article  CAS  PubMed  Google Scholar 

  209. Wang M, Jiang L, Monticone RE et al (2014) Proinflammation: the key to arterial aging. Trends Endocrinol Metab 25(2):72–79

    Article  CAS  PubMed  Google Scholar 

  210. Wang M, Zhang J, Telljohann R et al (2012) Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure. Hypertension 60(2):459–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Ungvari Z, Bailey-Downs L, Sosnowska D et al (2011) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301(2):H363–H372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Csiszar A, Wang M, Lakatta EG et al (2008) Inflammation and endothelial dysfunction during aging: role of NF-kappaB. J Appl Physiol 105(4):1333–1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Wang M, Wang HH, Lakatta EG (2013) Milk fat globule epidermal growth factor VIII signaling in arterial wall remodeling. Curr Vasc Pharmacol 11(5):768–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Lebreton JP, Joisel F, Raoult JP et al (1979) Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant. J Clin Invest 64(4):1118–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Gangneux C, Daveau M, Hiron M et al (2003) The inflammation-induced down-regulation of plasma Fetuin-A (alpha2HS-Glycoprotein) in liver results from the loss of interaction between long C/EBP isoforms at two neighbouring binding sites. Nucleic Acids Res 31(20):5957–5970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Cozzolino M, Gallieni M, Brancaccio D (2009) Inflammation and vascular calcification in chronic kidney disease: the role of Fetuin-A. Cytokine 45(2):70–71

    Article  CAS  PubMed  Google Scholar 

  217. Memoli B, Salerno S, Procino A et al (2010) A translational approach to micro-inflammation in end-stage renal disease: molecular effects of low levels of interleukin-6. Clin Sci (Lond) 119(4):163–174

    Article  CAS  Google Scholar 

  218. Davies MR, Lund RJ, Hruska KA (2003) BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol 14(6):1559–1567

    Google Scholar 

  219. Bobryshev YV (2005) Transdifferentiation of smooth muscle cells into chondrocytes in atherosclerotic arteries in situ: implications for diffuse intimal calcification. J Pathol 205 (5):641–650

    Google Scholar 

  220. Rattazzi M, Bennett BJ, Bea F et al (2005) Calcification of advanced atherosclerotic lesions in the innominate arteries of ApoE-deficient mice: potential role of chondrocyte-like cells. Arterioscler Thromb Vasc Biol 25 (7):1420–1425

    Google Scholar 

  221. Kawata T, Nagano N, Obi M et al (2008) Cinacalcet suppresses calcification of the aorta and heart in uremic rats. Kidney Int 74 (10):1270–1277

    Google Scholar 

  222. Koleganova N, Piecha G, Ritz E et al (2009) A calcimimetic (R-568), but not calcitriol, prevents vascular remodeling in uremia. Kidney Int 75(1):60–71

    Google Scholar 

  223. Doehring LC, Heeger C, Aherrahrou Z et al (2010) Myeloid CD34+CD13+ precursor cells transdifferentiate into chondrocyte-like cells in atherosclerotic intimal calcification. Am J Pathol 177(1):473–480

    Google Scholar 

  224. Fitzpatrick LA, Severson A, Edwards WD et al (1994) Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis. J Clin Invest 94(4):1597–1604

    Google Scholar 

  225. Giachelli CM, Bae N, Almeida M et al (1993) Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest 92(4):1686–1696

    Google Scholar 

  226. Moe SM, O’Neill KD, Duan D et al (2002) Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 61(2):638–647

    Google Scholar 

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Acknowledgements

Apologies to all authors whose important contributions could not be cited due to space restrictions.

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  1. Department of Nephrology, The Royal Melbourne Hospital, Parkville, VIC, 3050, Australia

    Edward R. Smith

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  1. Royal Hospital Melbourne Dept. Nephrology, Melbourne, Victoria, Australia

    Tim D. Hewitson

  2. Department of Nephrology, Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia

    Edward R. Smith

  3. Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia

    Stephen G. Holt

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Smith, E.R. (2016). Vascular Calcification in Uremia: New-Age Concepts about an Old-Age Problem. In: Hewitson, T., Smith, E., Holt, S. (eds) Kidney Research. Methods in Molecular Biology, vol 1397. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3353-2_13

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