Skip to main content

Advertisement

SpringerLink
Log in

Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature

  • Kidney and Bone (SM Moe and IB Salusky, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Vascular calcification is highly prevalent in patients with chronic kidney disease (CKD) and increases mortality in those patients. Impaired calcium and phosphate homeostasis, increased oxidative stress, and loss of calcification inhibitors have been linked to vascular calcification in CKD. Additionally, impaired bone may perturb serum calcium/phosphate and their key regulator, parathyroid hormone, thus contributing to increased vascular calcification in CKD. Therapeutic approaches for CKD, such as phosphate binders and bisphosphonates, have been shown to ameliorate bone loss as well as vascular calcification. The precise mechanisms responsible for vascular calcification in CKD and the contribution of bone metabolism to vascular calcification have not been elucidated. This review discusses the role of systemic uremic factors and impaired bone metabolism in the pathogenesis of vascular calcification in CKD. The regulation of the key osteogenic transcription factor Runt-related transcription factor 2 (Runx2) and the emerging role of Runx2-dependent receptor activator of nuclear factor kappa-B ligand (RANKL) in vascular calcification of CKD are emphasized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Moe SM. Vascular calcification and renal osteodystrophy relationship in chronic kidney disease. European journal of clinical investigation 2006;2006/08/04:51–62.

  2. Massy ZA, Maziere C, Kamel S, Brazier M, Choukroun G, Tribouilloy C, et al. Impact of inflammation and oxidative stress on vascular calcifications in chronic kidney disease. Pediatr Nephrol. 2005;20:380–2.

    Article  CAS  PubMed  Google Scholar 

  3. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69:1945–53.

    Article  CAS  PubMed  Google Scholar 

  4. Goodman WG, London G, Amann K, Block GA, Giachelli C, Hruska KA, et al. Vascular calcification in chronic kidney disease. Am J Kidney Dis. 2004;43:572–9.

    Article  PubMed  Google Scholar 

  5. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2003;2003/08/26:1731–40.

  6. Lau WL, Linnes M, Chu EY, Foster BL, Bartley BA, Somerman MJ, et al. High phosphate feeding promotes mineral and bone abnormalities in mice with chronic kidney disease. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2013;2012/10/10:62–9. Recapitulate full aspects of bone mineral disorders in chornic kidney diseases using high phosphate diet-fed mouse model.

  7. Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation. 1999;100:2168–76.

    Article  CAS  PubMed  Google Scholar 

  8. Giachelli CM. Mechanisms of vascular calcification in uremia. Seminars in nephrology 2004;2004/10/19:401–2.

  9. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011;2011/05/20:317–25.

  10. Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed? Arteriosclerosis, thrombosis, and vascular biology 2014;2014/02/22:724–36.

  11. Kelly-Arnold A, Maldonado N, Laudier D, Aikawa E, Cardoso L, Weinbaum S. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proceedings of the National Academy of Sciences of the United States of America 2013;2013/06/05:10741–6.

  12. Rodriguez-Garcia M, Gomez-Alonso C, Naves-Diaz M, Diaz-Lopez JB, Diaz-Corte C, Cannata-Andia JB. Vascular calcifications, vertebral fractures and mortality in haemodialysis patients. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association 2009;2008/08/30:239–46.

  13. Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V. Aortic calcification and the risk of osteoporosis and fractures. The Journal of clinical endocrinology and metabolism 2004;2004/09/10:4246–53.

  14. Reynolds JL, Skepper JN, McNair R, Kasama T, Gupta K, Weissberg PL, et al. Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol. 2005;16:2920–30.

    Article  CAS  PubMed  Google Scholar 

  15. Roman-Garcia P, Carrillo-Lopez N, Fernandez-Martin JL, Naves-Diaz M, Ruiz-Torres MP, Cannata-Andia JB. High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression. Bone 2010;2009/09/24:121–8.

  16. Mody N, Parhami F, Sarafian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radical Biol Med. 2001;31:509–19.

    Article  CAS  Google Scholar 

  17. Byon CH, Javed A, Dai Q, Kappes JC, Clemens TL, Darley-Usmar VM, et al. Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J Biol Chem. 2008;283:15319–27.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Maziere C, Savitsky V, Galmiche A, Gomila C, Massy Z, Maziere JC. Oxidized low density lipoprotein inhibits phosphate signaling and phosphate-induced mineralization in osteoblasts. Involvement of oxidative stress. Biochim Biophys Acta. 1802;2010:1013–9.

    Google Scholar 

  19. Yang S, Feskanich D, Willett WC, Eliassen AH, Wu T. Association between global biomarkers of oxidative stress and hip fracture in postmenopausal women: a prospective study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2014;2014/06/25:2577–83. Reports epidemiologic study showing an association of oxidative stress with bone fracture in postmenopausal women using newly developed biomarkers of oxidative stress.

  20. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. The Journal of clinical endocrinology and metabolism 2006;2006/06/01:3144–9.

  21. Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss E, Bricker NS. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake. Kidney international 1972;1972/09/01:147–51.

  22. Estepa JC, Aguilera-Tejero E, Lopez I, Almaden Y, Rodriguez M, Felsenfeld AJ. Effect of phosphate on parathyroid hormone secretion in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 1999;1999/11/26:1848–54.

  23. Liu F, Fu P, Fan W, Gou R, Huang Y, Qiu H, et al. Involvement of parathyroid hormone-related protein in vascular calcification of chronic haemodialysis patients. Nephrology (Carlton, Vic) 2012;2012/03/28:552–60.

  24. Patidar A, Singh DK, Winocour P, Farrington K, Baydoun AR. Human uraemic serum displays calcific potential in vitro that increases with advancing chronic kidney disease. Clinical science (London, England : 1979) 2013;2013/03/08:237–45.

  25. Kurz P, Monier-Faugere MC, Bognar B, Werner E, Roth P, Vlachojannis J, et al. Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney international 1994;1994/09/01:855–61.

  26. Mathew S, Davies M, Lund R, Saab G, Hruska KA. Function and effect of bone morphogenetic protein-7 in kidney bone and the bone-vascular links in chronic kidney disease. European journal of clinical investigation 2006;2006/08/04:43–50.

  27. Elder G. Pathophysiology and recent advances in the management of renal osteodystrophy. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 2002;2002/12/10:2094–105.

  28. Huang JC, Sakata T, Pfleger LL, Bencsik M, Halloran BP, Bikle DD, et al. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res. 2004;19:235–44.

    Article  CAS  PubMed  Google Scholar 

  29. Hruska KA, Saab G, Mathew S, Lund R. Renal osteodystrophy, phosphate homeostasis, and vascular calcification. Seminars in dialysis 2007;2007/07/20:309–15.

  30. Elmariah S, Delaney JA, O'Brien KD, Budoff MJ, Vogel-Claussen J, Fuster V, et al. Bisphosphonate use and prevalence of valvular and vascular calcification in women MESA (The Multi-Ethnic Study of Atherosclerosis). Journal of the American College of Cardiology 2010;2010/11/13:1752–9.

  31. Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arteriosclerosis, thrombosis, and vascular biology 2001;2001/05/23:817–24.

  32. Helas S, Goettsch C, Schoppet M, Zeitz U, Hempel U, Morawietz H, et al. Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol. 2009;175:473–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Ishimura E, Taniwaki H, Tabata T, Tsujimoto Y, Jono S, Emoto M, et al. Cross-sectional association of serum phosphate with carotid intima-medial thickness in hemodialysis patients. American journal of kidney diseases : the official journal of the National Kidney Foundation 2005;2005/04/30:859–65.

  34. 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;2003/03/19:827–33.

  35. Lomashvili KA, Khawandi W, O'Neill WC. Reduced plasma pyrophosphate levels in hemodialysis patients. Journal of the American Society of Nephrology : JASN 2005;2005/06/17:2495-500.

  36. 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;89:755–64.

    Article  CAS  PubMed  Google Scholar 

  37. Byon CH, Sun Y, Chen J, Yuan K, Mao X, Heath JM, et al. Runx2-upregulated receptor activator of nuclear factor kappaB ligand in calcifying smooth muscle cells promotes migration and osteoclastic differentiation of macrophages. Arteriosclerosis, thrombosis, and vascular biology 2011;2011/04/02:1387-96. Report a direct regulation of RANKL by Runx2 in smooth muscle cells which promotes the migration and osteoclastic differentiation of macrophages.

  38. Sun Y, Byon CH, Yuan K, Chen J, Mao X, Heath JM, et al. Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res. 2012;111:543–52. Determine that smooth muscle-specific deletion of Runx2 inhibited vascular calcification in mice and uncover a coupling beteen vascualr osteoclasts with vascualr calcification in atherolscelrosis.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Li X, Giachelli CM. Sodium-dependent phosphate cotransporters and vascular calcification. Curr Opin Nephrol Hypertens. 2007;16:325–8.

    Article  PubMed  Google Scholar 

  40. Moe SM, Duan D, Doehle BP, O'Neill KD, Chen NX. Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int. 2003;63:1003–11.

    Article  CAS  PubMed  Google Scholar 

  41. Chen NX, Duan D, O'Neill KD, Wolisi GO, Koczman JJ, Laclair R, et al. The mechanisms of uremic serum-induced expression of bone matrix proteins in bovine vascular smooth muscle cells. Kidney international 2006;2006/07/14:1046–53.

  42. Larsson TE, Olauson H, Hagstrom E, Ingelsson E, Arnlov J, Lind L, et al. Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arteriosclerosis, thrombosis, and vascular biology 2010;2009/12/02:333–9.

  43. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 2005;2005/10/26:2627–33.

  44. Tuttle KR, Short RA. Longitudinal relationships among coronary artery calcification, serum phosphorus, and kidney function. Clinical journal of the American Society of Nephrology : CJASN 2009;2009/12/08:1968–73.

  45. West SL, Swan VJ, Jamal SA. Effects of calcium on cardiovascular events in patients with kidney disease and in a healthy population. Clinical journal of the American Society of Nephrology : CJASN 2010;2010/02/03:S41–S47.

  46. Pai A, Leaf EM, El-Abbadi M, Giachelli CM. 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. 2011;178:764–73. Determine smooth muscle phenotype change in medial vascualr clacificaiton in mouse CKD model.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Lomashvili K, Garg P, O'Neill WC. Chemical and hormonal determinants of vascular calcification in vitro. Kidney international 2006;2006/03/15:1464–70.

  48. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circulation research 2000;2000/09/29:E10–E17.

  49. Li X, Yang HY, Giachelli CM. Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circulation research 2006;2006/03/11:905–12.

  50. Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, et al. 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. Journal of the American Society of Nephrology : JASN 2004;2004/10/27:2857–67.

  51. Yang H, Curinga G, Giachelli CM. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro. Kidney international 2004;2004/12/01:2293–9.

  52. Yamada S, Taniguchi M, Tokumoto M, Toyonaga J, Fujisaki K, Suehiro T, et al. The antioxidant tempol ameliorates arterial medial calcification in uremic rats: important role of oxidative stress in the pathogenesis of vascular calcification in chronic kidney disease. J Bone Miner Res. 2012;27:474–85. Demonstrate that uremia-induced oxidative stress in rats with chronic kidney disease results in the development of aortic calcification, which can be ameliorated by use of tempol, an antioxidant.

    Article  CAS  PubMed  Google Scholar 

  53. Yin H, Shi ZG, Yu YS, Hu J, Wang R, Luan ZP, et al. Protection against osteoporosis by statins is linked to a reduction of oxidative stress and restoration of nitric oxide formation in aged and ovariectomized rats. European journal of pharmacology 2012;2011/12/02:200–6.

  54. Goettsch C, Rauner M, Hamann C, Sinningen K, Hempel U, Bornstein SR, et al. Nuclear factor of activated T cells mediates oxidised LDL-induced calcification of vascular smooth muscle cells. Diabetologia 2011;2011/06/28:2690–701.

  55. Deng L, Huang L, Sun Y, Heath JM, Wu H, Chen Y. Inhibition of FOXO1/3 promotes vascular calcification. Arterioscler Thromb Vasc Biol 2014.

  56. Heiss A, DuChesne A, Denecke B, Grotzinger J, Yamamoto K, Renne T, et al. Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. The Journal of biological chemistry 2003;2003/01/31:13333–41.

  57. 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. The Journal of clinical investigation 2003;2003/08/05:357–66.

  58. Sage AP, Lu J, Tintut Y, Demer LL. Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney international 2011;2010/10/15:414–22. Determine the effects and potential mecahnisms of Fetuin-A in inhibiting hyperphosphatemia-induced calcification of vascular smooth muscle cells

  59. veKemik POF. The relationship between fetuin-a and bone mineral density in postmenopausal. Osteoporosis. 2013;28:195–201.

    Google Scholar 

  60. Terkeltaub RA. Inorganic pyrophosphate generation and disposition in pathophysiology. American journal of physiology Cell physiology 2001;2001/06/13:C1-c11.

  61. Lomashvili KA, Narisawa S, Millan JL, O'Neill WC. Vascular calcification is dependent on plasma levels of pyrophosphate. Kidney international 2014;2014/04/11:1351–6.

  62. Osorio A, Ortega E, Torres JM, Sanchez P, Ruiz-Requena E. Biochemical markers of vascular calcification in elderly hemodialysis patients. Mol Cell Biochem. 2013;374:21–7.

    Article  CAS  PubMed  Google Scholar 

  63. Montanez-Barragan A, Gomez-Barrera I, Sanchez-Nino MD, Ucero AC, Gonzalez-Espinoza L, Ortiz A. Osteoprotegerin and kidney disease. J Nephrol 2014.

  64. Siomou E, Challa A, Printza N, Giapros V, Petropoulou F, Mitsioni A, et al. Serum osteoprotegerin, RANKL and fibroblast growth factor-23 in children with chronic kidney disease. Pediatr Nephrol. 2011;26:1105–14.

    Article  PubMed  Google Scholar 

  65. Walsh MC, Choi Y. Biology of the TRANCE axis. Cytokine Growth Factor Rev. 2003;14:251–63.

    Article  CAS  PubMed  Google Scholar 

  66. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Orita Y, Yamamoto H, Kohno N, Sugihara M, Honda H, Kawamata S, et al. Role of osteoprotegerin in arterial calcification: development of new animal model. Arteriosclerosis, thrombosis, and vascular biology 2007;2007/07/07:2058–64.

  68. Osako MK, Nakagami H, Koibuchi N, Shimizu H, Nakagami F, Koriyama H, et al. Estrogen inhibits vascular calcification via vascular RANKL system: common mechanism of osteoporosis and vascular calcification. Circ Res. 2010;107:466–75.

    Article  CAS  PubMed  Google Scholar 

  69. Mohammadpour AH, Shamsara J, Nazemi S, Ghadirzadeh S, Shahsavand S, Ramezani M. Evaluation of RANKL/OPG serum concentration ratio as a new biomarker for coronary artery calcification: a pilot study. Thrombosis. 2012;2012:306263.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Morony S, Tintut Y, Zhang Z, Cattley RC, Van G, Dwyer D, et al. Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(-/-) mice. Circulation. 2008;117:411–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, et al. Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2008;2008/02/08:2465–75.

  72. Osako MK, Nakagami H, Shimamura M, Koriyama H, Nakagami F, Shimizu H, et al. Cross-talk of receptor activator of nuclear factor-kappaB ligand signaling with renin-angiotensin system in vascular calcification. Arteriosclerosis, thrombosis, and vascular biology 2013;2013/04/13:1287–96.

  73. Rinotas V, Niti A, Dacquin R, Bonnet N, Stolina M, Han CY, et al. Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 2014;2013/10/16:1158-69. Develop a mouse model harboring human RANKL and demonstrates a correlation of the levels of transgenic RANKL with the severity of osteoporotic phenotypes.

  74. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–65.

    Article  CAS  PubMed  Google Scholar 

  75. Samelson EJ, Miller PD, Christiansen C, Daizadeh NS, Grazette L, Anthony MS, et al. RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk. J Bone Miner Res. 2014;29:450–7. Demonstrate the effects of RANKL antibody on osteoporosis and aortic calcification in postmenopausal women with advnced age. Although it shows RANKL antibody has no overall effects on 3-year progression of aortic calficiation, it appears to inhibit calcification in patients with less calcification and increase calcificaiton in patients with severe calcification, suggesting different.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Panizo S, Cardus A, Encinas M, Parisi E, Valcheva P, Lopez-Ongil S, et al. RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ Res. 2009;104:1041–8.

    Article  CAS  PubMed  Google Scholar 

  77. Deuell KA, Callegari A, Giachelli CM, Rosenfeld ME, Scatena M. RANKL enhances macrophage paracrine pro-calcific activity in high phosphate-treated smooth muscle cells: dependence on IL-6 and TNF-alpha. Journal of vascular research 2012;2012/09/06:510–21. Determine a role of pro-calcific cytokines produced by macrophages via RANKL signaling in promoting calcification of smooth muscle cells.

  78. Lin HH, Liou HH, Wu MS, Lin CY, Huang CC. Long-term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients. Nephrology (Carlton, Vic) 2014;2014/08/13:672–8.

  79. Tokumoto M, Mizobuchi M, Finch JL, Nakamura H, Martin DR, Slatopolsky E. Blockage of the renin-angiotensin system attenuates mortality but not vascular calcification in uremic rats: sevelamer carbonate prevents vascular calcification. American journal of nephrology 2009;2009/01/16:582–91.

  80. Phan O, Ivanovski O, Nguyen-Khoa T, Mothu N, Angulo J, Westenfeld R, et al. Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E-deficient mice. Circulation. 2005;112:2875–82.

    Article  CAS  PubMed  Google Scholar 

  81. Nikolov IG, Joki N, Nguyen-Khoa T, Guerrera IC, Maizel J, Benchitrit J, et al. Lanthanum carbonate, like sevelamer-HCl, retards the progression of vascular calcification and atherosclerosis in uremic apolipoprotein E-deficient mice. Nephrol Dial Transplant. 2012;27:505–13. Demonstrate the effects of a phosphate binder on vascular calcification in CKD mouse model.

    Article  CAS  PubMed  Google Scholar 

  82. Ciceri P, Elli F, Brenna I, Volpi E, Romagnoli S, Tosi D, et al. Lanthanum prevents high phosphate-induced vascular calcification by preserving vascular smooth muscle lineage markers. Calcified tissue international 2013;2013/02/19:521–30.

  83. Ohtake T, Kobayashi S, Oka M, Furuya R, Iwagami M, Tsutsumi D, et al. Lanthanum carbonate delays progression of coronary artery calcification compared with calcium-based phosphate binders in patients on hemodialysis: a pilot study. Journal of cardiovascular pharmacology and therapeutics 2013;2013/04/26:439–46.

  84. Alam S, Hussain A, Daiwajna R, Tan J. Clinical efficacy of sevelamer hydrochloride in patients with end-stage renal disease: a retrospective study. Singapore medical journal 2013;2013/05/30:263–6.

  85. Raggi P, James G, Burke SK, Bommer J, Chasan-Taber S, Holzer H, et al. Decrease in thoracic vertebral bone attenuation with calcium-based phosphate binders in hemodialysis. J Bone Miner Res. 2005;20:764–72.

    Article  CAS  PubMed  Google Scholar 

  86. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney international 2007;2007/01/04:438–41.

  87. McCullough PA, Chinnaiyan KM. Annual progression of coronary calcification in trials of preventive therapies: a systematic review. Arch Intern Med. 2009;169:2064–70.

    Article  CAS  PubMed  Google Scholar 

  88. Alam MU, Kirton JP, Wilkinson FL, Towers E, Sinha S, Rouhi M, et al. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovascular research 2009;2008/10/15:260–8.

  89. Henaut L, Boudot C, Massy ZA, Lopez-Fernandez I, Dupont S, Mary A, et al. Calcimimetics increase CaSR expression and reduce mineralization in vascular smooth muscle cells: mechanisms of action. Cardiovascular research 2014;2013/11/13:256–65.

  90. Ciceri P, Volpi E, Brenna I, Elli F, Borghi E, Brancaccio D, et al. The combination of lanthanum chloride and the calcimimetic calindol delays the progression of vascular smooth muscle cells calcification. Biochemical and biophysical research communications 2012;2012/02/09:770–3.

  91. Ivanovski O, Nikolov IG, Joki N, Caudrillier A, Phan O, Mentaverri R, et al. The calcimimetic R-568 retards uremia-enhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE-/-) mice. Atherosclerosis 2009;2009/01/03:55–62.

  92. Henley C, Davis J, Miller G, Shatzen E, Cattley R, Li X, et al. The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats. European journal of pharmacology 2009;2009/05/28:306–13.

  93. Nakayama K, Nakao K, Takatori Y, Inoue J, Kojo S, Akagi S, et al. Long-term effect of cinacalcet hydrochloride on abdominal aortic calcification in patients on hemodialysis with secondary hyperparathyroidism. International journal of nephrology and renovascular disease 2013;2014/01/01:25–33.

  94. Raggi P, Chertow GM, Torres PU, Csiky B, Naso A, Nossuli K, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2011;2010/12/15:1327–39.

  95. Mori K, Shioi A, Jono S, Nishizawa Y, Morii H. Expression of matrix Gla protein (MGP) in an in vitro model of vascular calcification. FEBS Lett. 1998;433:19–22.

    Article  CAS  PubMed  Google Scholar 

  96. Zhou S, Fang X, Xin H, Guan S. Effects of alendronate on the Notch1RBPJkappa signaling pathway in the osteogenic differentiation and mineralization of vascular smooth muscle cells. Molecular medicine reports 2013;2013/05/28:89–94.

  97. Hashiba H, Aizawa S, Tamura K, Kogo H. Inhibition of the progression of aortic calcification by etidronate treatment in hemodialysis patients: long-term effects. Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 2006;2006/03/25:59–64.

  98. Hartle JE, Tang X, Kirchner HL, Bucaloiu ID, Sartorius JA, Pogrebnaya ZV, et al. Bisphosphonate therapy, death, and cardiovascular events among female patients with CKD: a retrospective cohort study. American journal of kidney diseases : the official journal of the National Kidney Foundation 2012;2012/01/17:636–44.

  99. Tanko LB, Qin G, Alexandersen P, Bagger YZ, Christiansen C. Effective doses of ibandronate do not influence the 3-year progression of aortic calcification in elderly osteoporotic women. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2005;2004/06/16:184–90.

  100. Toussaint ND, Lau KK, Strauss BJ, Polkinghorne KR, Kerr PG. Effect of alendronate on vascular calcification in CKD stages 3 and 4: a pilot randomized controlled trial. American journal of kidney diseases : the official journal of the National Kidney Foundation 2010;2010/03/30:57–68.

Download references

Acknowledgments

Due to the scope and limitation, we apologize for not being able to include all the important work in the field. The authors thank Jay M. McDonald, MD (University of Alabama at Birmingham, UAB) for critical review. The original research programs of the authors are supported by grants from the National Institutes of Health, HL092215 and DK100847, and Veterans Administration BX000369 and BX001591 (project 2) to YC.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

CH Byon and Y Chen both declare no conflicts of interest.

Human and Animal Rights and Informed Consent

All studies by the authors involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Alabama at Birmingham, 614 Shelby Biomedical Research Bldg., 1825 University Blvd., Birmingham, AL, 35294, USA

    Chang Hyun Byon & Yabing Chen

  2. Department of Pathology, Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35294, USA

    Yabing Chen

Authors
  1. Chang Hyun Byon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yabing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yabing Chen.

Additional information

This article is part of the Topical Collection on Kidney and Bone

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Byon, C.H., Chen, Y. Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature. Curr Osteoporos Rep 13, 206–215 (2015). https://doi.org/10.1007/s11914-015-0270-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-015-0270-3

Keyword

Search

Navigation