Seminars in Nephrology
Volume 29, Issue 2 , Pages 156-165 , March 2009

The Pathogenesis of Vascular Calcification in the Chronic Kidney Disease Mineral Bone Disorder: The Links Between Bone and the Vasculature

  • Keith A. Hruska, MD

      Affiliations

    • Department of Pediatrics, Division of Nephrology, Washington University School of Medicine, St. Louis, MO
    • Department of Internal Medicine, Division of Nephrology, Washington University School of Medicine, St. Louis, MO
    • Corresponding Author InformationAddress reprint requests to Keith A. Hruska, MD, Department of Pediatrics, Washington University School of Medicine, Campus Box 8208, 5th Floor MPRB, 660 S. Euclid Ave, St. Louis, MO 63110
  • ,
  • Suresh Mathew, MD

      Affiliations

    • Department of Pediatrics, Division of Nephrology, Washington University School of Medicine, St. Louis, MO
  • ,
  • Richard J. Lund, MD

      Affiliations

    • Renal Division, Department of Medicine, Creighton University, Omaha, NE
  • ,
  • Imran Memon, MD

      Affiliations

    • Department of Pediatrics, Division of Nephrology, Washington University School of Medicine, St. Louis, MO
  • ,
  • Georges Saab, MD

      Affiliations

    • Department of Internal Medicine, Division of Nephrology, Washington University School of Medicine, St. Louis, MO

References 

  1. Ejerblad S, Ericsson JLE, Eriksson I. Arterial lesions of the radial artery in uraemic patients. Acta Chir Scand. 1979;145:415–428
  2. Elliott RJ, McGrath LT. Calcification of the human aorta during aging. Calcif Tissue Int. 1994;54:268–273
  3. Edmonds ME. Medial arterial calcification and diabetes mellitus. Z Kardiol. 2000;89:II/101-4
  4. Blacher J, Safar ME, Guerin AP, Pannier B, Marchais SJ, London GM. Aortic pulse wave velocity index and mortality in end-stage renal disease. Kidney Int. 2003;63:1852–1860
  5. Raggi P, Boulay A, Chasan-Taber S, Amin N, Dillon M, Burke SK, et al. Cardiac calcification in adult hemodialysis patients (A link between end-stage renal disease and cardiovascular disease?). J Am Coll Cardiol. 2002;39:695–701
  6. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478–1483
  7. Cheng H, Jiang W, Phillips FM, Haydon RC, Peng Y, Zhou L, et al. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg. 2003;85:1544–1552
  8. Kato M, Patel MS, Levasseur R, Lobov I, Chang BHJ, Glass DA, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol. 2002;157:303–314
  9. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–764
  10. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17–29
  11. Satokata I, Mass R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet. 1994;6:348–356
  12. Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet. 2004;24:391–395
  13. Towler DA, Bidder M, Latifi T, Coleman T, Semenkovich CF. Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice. J Biol Chem. 1998;273:30427–30434
  14. Tyson KL, Reynolds JL, McNair R, Zhang Q, Weissberg PL, Shanahan CM. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol. 2003;23:489–494
  15. Moe SM, O'Neill KD, Duan D, Ahmed S, Chen NX, Leapman SB, et al. Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int. 2002;61:638–647
  16. Hedin U, Roy J, Tran PK, Lundmark K, Rahman A. Control of smooth muscle cell proliferation—the role of the basement membrane. Thromb Haemost. 1999;82(Suppl):23–26
  17. Worth NF, Rolfe BE, Song J, Campbell R. Vascular smooth muscle cell phenotypic modulation in culture is associated with reorganization of contractile and cytoskeletal proteins. Cell Motil Cytoskeleton. 2001;49:130–145
  18. Thyberg J. Differentiated properties and proliferation of arterial smooth muscle cells in culture. Int Rev Cytol. 1996;169:183–265
  19. Brennan MJ, Millis AJ, Fritz KE. Fibronectin inhibits morphological changes in vascular smooth muscle cells. J Cell Physiol. 1982;112:284–290
  20. Barone LM, Owen TA, Tassinari MS. Developmental expression and hormonal regulation of the rat matrix gla protein (MGP) gene in chondrogenesis and osteogenesis. J Cell Biochem. 1991;46:351–365
  21. Boström K, Watson KE, Horn S, Worthman C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest. 1993;91:1800–1809
  22. Shioi A, Nishizawa Y, Jono S, Koyama H, Hosoi M, Morii H. b-Glycerophosphate accelerates calcification in cultured bovine vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1995;15:2003–2009
  23. Mathew S, Tustison KS, Sugatani T, Chaudhary LR, Rifas L, Hruska KA. The mechanism of phosphorus as a cardiovascular risk factor in chronic kidney disease. J Am Soc Nephrol. 2008;19:1092–1105
  24. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res. 2000;87:e10–e17
  25. Chen NX, O'Neill KD, Duan D, Moe SM. Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int. 2002;62:1724–1731
  26. Roy ME, Nishimoto SK. Matrix Gla protein binding to hydroxyapatite is dependent on the ionic environment: calcium enhances binding affinity but phosphate and magnesium decrease affinity. Bone. 2002;31:296–302
  27. Yagami K, Suh JY, Enomoto-Iwamoto M, Koyama E, Abrams WR, Shapiro IM, et al. Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb. J Cell Biol. 1999;147:1097–1108
  28. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78–81
  29. Steitz SA, Speer MY, Curinga G, Yang H-Y, Haynes P, Aebersold R, et al. Smooth muscle cell phenotypic transition associated with calcification. Circ Res. 2001;89:1147–1154
  30. Bostrom K, Tsao D, Shen S, Wang Y, Demer LL. Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells. J Biol Chem. 2001;276:14044–14052
  31. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpleyl J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260–1268
  32. Nakamura M, Udagawa N, Matsuura S, Mogi M, Nakamura H, Horiuchi H, et al. Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption. Endocrinology. 2003;144:5441–5449
  33. Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000;192:463–474
  34. Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoc A, Kilic R, et al. Receptor activator of nuclear factor kB ligand and osteoprotegerin regulate aortic valve calcification*1. J Mol Cell Cardiol. 2004;36:57–66
  35. Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000;20:317–327
  36. Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol. 2001;21:817–824
  37. Price PA, June HH, Buckley JR, Williamson MK. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol. 2001;21:1610–1616
  38. Erben RG, Scutt AM, Miao D, Kollenkirchen U, Haberey M. Short-term treatment of rats with high dose 1,25-dihydroxyvitamin D3 stimulates bone formation and increases the number of osteoblast precursor cells in bone marrow. Endocrinology. 1997;138:4629–4635
  39. Price PA, June HH, Buckley JR, Williamson MK. SB 242784, a selective inhibitor of the osteoclastic V-H+-ATPase, inhibits arterial calcification in the rat. Circ Res. 2002;91:547–552
  40. Kitazawa S, Kajimoto K, Kondo T, Kitazawa R. Vitamin D3 supports osteoclastogenesis via functional vitamin d response element of human RANKL gene promoter. J Cell Biochem. 2003;89:771–777
  41. Mathew S, Strebeck F, Hruska KA. The protective actions of vitamin D analogs in the vascular calcification of chronic kidney disease (CKD). J Am Soc Nephrol. In press.
  42. Elzanowski A, Barker WC, Hunt LT, Seibel-Ross E. Cystatin domains in alpha-2-HS glycoprotein and fetuin. FEBS Lett. 1988;227:167–170
  43. Schinke T, Amendt C, Trindl A, Poschke O, Muller-Esterl W, Jahnen-Dechent W. The serum protein a2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. J Biol Chem. 1996;271:20789–20796
  44. Demetriou M, Binkert C, Sukhu B, Tenenbaum HD, Dennis JW. Fetuin/alpha2-HS glycoprotein is transforming growth factor-beta type II receptor mimic and cytokine antagonist. J Biol Chem. 1996;271:12755–12761
  45. Binkert C, Demetriou M, Sukhu B, Szweras M, Tennenbaum HC, Dennis JW. Regulation of osteogenesis by fetuin. J Biol Chem. 1999;274:28514–28520
  46. Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, et al. The serum protein {alpha}2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest. 2003;112:357–366
  47. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet. 2003;361:827–833
  48. Lebreton JP, Joisel F, Raoult JP, Lannuzel B, Rogez JP, Humbert G. 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. 1979;64:1118–1129
  49. Simon M, Maresh JG, Harris SE, Hernandez JD, Arar M, Olson MS, et al. Expression of bone morphogenetic protein-7 mRNA in normal and ischemic adult rat kidney. Am J Physiol. 1999;276:F382–F389
  50. Wang S, Chen Q, Simon TC, Strebeck F, Chaudhary L, Morrissey J, et al. Bone morphogenetic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int. 2003;63:2037–2049
  51. Wang S, Hirschberg R. Loss of renal tubular BMP7 during the evolution of experimental diabetic nephropathy. J Am Soc Nephrol. 2000;11:655A
  52. Davies MR, Lund RJ, Mathew S, Hruska KA. Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome. J Am Soc Nephrol. 2005;16:917–928
  53. Gonzalez EA, Lund RJ, Martin KJ, McCartney JE, Tondravi MM, Sampath TK, et al. Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7. Kidney Int. 2002;61:1322–1331
  54. Davies MR, Lund RJ, Hruska KA. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol. 2003;14:1559–1567
  55. Dorai H, Vukicevic S, Sampath TK. Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro. J Cell Physiol. 2000;184:37–45
  56. Kokubo T, Uchida H, Chasnoff SE, Matthew S, Hruska KA, Choi ET. Chronic kidney disease (CKD) accelerates development of neointimal hyperplasia in a mouse arteriovenous fistula model. J Am Soc Nephrol. In press.
  57. White KE, Evans WE, O'Riordan JLH, Speer MC, Econs MJ, Lorenz-Depiereux B, et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–348
  58. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001;98:6500–6505
  59. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of FGF23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113:561–568
  60. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 2003;64:2272–2279
  61. Weber TJ, Liu S, Indridason OS, Quarles LD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res. 2003;18:1227–1234
  62. Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J. 2006;20:720–722
  63. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–592
  64. Wang L, Banu J, Mcmahan CA, Kalu DN. Male rodent model of age-related bone loss in men. Bone. 2001;29:141–148
  65. Clarke BL, Ebeling PR, Jones JD, Wahner HW, O'Fallon WM, Riggs BL, et al. Changes in quantitative bone histomorphometry in aging healthy men. J Clin Endocrinol Metab. 1996;81:2264–2270
  66. Suzuki K, Miyakoshi N, Tsuchida T, Kasukawa Y, Sato K, Itoi E. Effects of combined treatment of insulin and human parathyroid hormone(1-34) on cancellous bone mass and structure in streptozotocin-induced diabetic rats. Bone. 2003;33:108–114
  67. Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM. Bone loss and bone turnover in diabetes. Diabetes. 1995;44:775–782
  68. Shao JS, Cheng SL, Charlton-Kachigian N, Loewy AP, Towler DA. Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice. J Biol Chem. 2003;278:50195–50202
  69. Lund RJ, Davies MR, Brown AJ, Hruska KA. Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model. J Am Soc Nephrol. 2004;15:359–369
  70. Hruska KA, Saab G, Chaudhary LR, Quinn CO, Lund RJ, Surendran K. Kidney-bone, bone-kidney, and cell-cell communications in renal osteodystrophy. Semin Nephrol. 2004;24:25–38

 Supported by National Institutes of Health grants (DK070790, AR41677, and T32-DK062705 to K.A.H.), and by research support from Shire, Wayne, PA; Genzyme, Cambridge, MA; Abbott, Abbott Park, IL; and Fresenius, Waltham, MA.

PII: S0270-9295(09)00009-6

doi: 10.1016/j.semnephrol.2009.01.008

Seminars in Nephrology
Volume 29, Issue 2 , Pages 156-165 , March 2009