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RANKL–OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy

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Abstract

Type 2 diabetes is associated with increased cardiovascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vascular calcification being a major complication in the pathogenesis of this disease. Current research and drug targets in diabetes have hitherto focused on atherosclerosis, but vascular calcification is now recognised as an independent predictor of cardiovascular morbidity and mortality. An emerging regulatory pathway for vascular calcification in diabetes involves the receptor activator for nuclear factor κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Important novel biomarkers of calcification are related to levels of glycation and inflammation in diabetes. Several therapeutic strategies could have advantageous effects on the vasculature in patients with diabetes, including targeting the RANKL and receptor for AGE (RAGE) signalling pathways, since there has been little success—at least in macrovascular outcomes—with conventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL–RANK–OPG signalling, RAGE signalling and the associated proinflammatory milieu alters the natural course of cardiovascular complications and outcomes in people with diabetes. However, further research is critically needed to understand the precise mechanisms underpinning these pathways, in order to translate the anti-calcification strategies into patient benefit.

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Abbreviations

CKD:

Chronic kidney disease

GACI:

Generalised arterial calcification of infancy

OPG:

Osteoprotegerin

RAGE:

Receptor for AGE

RANK:

Receptor activator for nuclear factor κB

RANKL:

Receptor activator for nuclear factor κB ligand

VSMC:

Vascular smooth muscle cell

References

  1. King MR, Cooper GM, DeNevi D (2004) Who killed King Tut?: using modern forensics to solve a 3300-year-old mystery. Prometheus Books, Amherst

    Google Scholar 

  2. Allam AH, Thompson RC, Wann LS, Miyamoto MI, Thomas GS (2009) Computed tomographic assessment of atherosclerosis in ancient Egyptian mummies. JAMA J Am Med Assoc 302:2091–2094

    Article  Google Scholar 

  3. Alexander MY, Wilkinson FL, Kirton JP et al (2005) Identification and characterization of vascular calcification-associated factor, a novel gene upregulated during vascular calcification in vitro and in vivo. Arterioscler Thromb Vasc Biol 25:1851–1857

    Article  PubMed  CAS  Google Scholar 

  4. Kirton JP, Wilkinson FL, Canfield AE, Alexander MY (2006) Dexamethasone downregulates calcification-inhibitor molecules and accelerates osteogenic differentiation of vascular pericytes: implications for vascular calcification. Circ Res 98:1264–1272

    Article  PubMed  CAS  Google Scholar 

  5. Liu Y, Wang T, Yan J et al (2011) HGF/c-Met signalling promotes Notch3 activation and human vascular smooth muscle cell osteogenic differentiation in vitro. Atherosclerosis 219:440–447

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Ndip A, Williams A, Jude EB et al (2011) The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic Charcot neuroarthropathy. Diabetes 60:2187–2196

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Wilkinson FL, Liu Y, Rucka AK et al (2007) Contribution of VCAF-positive cells to neovascularization and calcification in atherosclerotic plaque development. J Pathol 211:362–369

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Yan J, Stringer SE, Hamilton A et al (2011) Decorin GAG synthesis and TGF-β signaling mediate Ox-LDL-induced mineralization of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:608–615

    Article  PubMed  CAS  Google Scholar 

  9. Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL (1993) Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 91:1800–1809

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  11. Giachelli CM, Speer MY, Li X, Rajachar RM, Yang H (2005) Regulation of vascular calcification: roles of phosphate and osteopontin. Circ Res 96:717–722

    Article  PubMed  CAS  Google Scholar 

  12. Proudfoot D, Shanahan CM (2006) Molecular mechanisms mediating vascular calcification: role of matrix Gla protein. Nephrology 11:455–461

    Article  PubMed  CAS  Google Scholar 

  13. Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME (1999) Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 100:2168–2176

    Article  PubMed  CAS  Google Scholar 

  14. Steitz SA, Speer MY, Curinga G et al (2001) Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 89:1147–1154

    Article  PubMed  CAS  Google Scholar 

  15. Tintut Y, Alfonso Z, Saini T et al (2003) Multilineage potential of cells from the artery wall. Circulation 108:2505–2510

    Article  PubMed  Google Scholar 

  16. Towler DA, Shao JS, Cheng SL, Pingsterhaus JM, Loewy AP (2006) Osteogenic regulation of vascular calcification. Ann N Y Acad Sci 1068:327–333

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Rezg R, Barreto FC, Barreto DV, Liabeuf S, Drueke TB, Massy ZA (2011) Inhibitors of vascular calcification as potential therapeutic targets. J Nephrol 24:416–427

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Hjortnaes J, New SE, Aikawa E (2013) Visualizing novel concepts of cardiovascular calcification. Trends Cardiovasc Med 23:71–79

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Rogers M, Goettsch C, Aikawa E (2013) Medial and intimal calcification in chronic kidney disease: stressing the contributions. J Am Heart Assoc 2:e000481

    Article  PubMed  PubMed Central  Google Scholar 

  22. Alexander MY, Heagerty AM, Keenan D (2008) Vascular calcification: characteristics and pathological mechanisms. In: Rowlands D, Clarke B (eds) Recent advances in cardiology, vol 15. Royal Society of Medicine Press, London, pp 21–43

    Google Scholar 

  23. Vattikuti R, Towler DA (2004) Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 286:E686–E696

    Article  PubMed  CAS  Google Scholar 

  24. Proudfoot D, Shanahan CM (2001) Biology of calcification in vascular cells: intima versus media. Herz 26:245–251

    Article  PubMed  CAS  Google Scholar 

  25. 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 29:327–337

    Article  PubMed  CAS  Google Scholar 

  26. Pai A, Leaf EM, El-Abbadi M, Giachelli CM (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. A J Pathol 178:764–773

    Article  CAS  Google Scholar 

  27. Wang SS, Martin LJ, Schadt EE et al (2009) Disruption of the aortic elastic lamina and medial calcification share genetic determinants in mice. Circ Cardiovasc Genet 2:573–582

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Reid DG, Shanahan CM, Duer MJ et al (2012) Lipids in biocalcification: contrasts and similarities between intimal and medial vascular calcification and bone by NMR. J Lipid Res 53:1569–1575

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Chen NX, Moe SM (2003) Arterial calcification in diabetes. Curr Diabetes Rep 3:28–32

    Article  Google Scholar 

  31. Costacou T, Huskey ND, Edmundowicz D, Stolk R, Orchard TJ (2006) Lower-extremity arterial calcification as a correlate of coronary artery calcification. Metab Clin Exp 55:1689–1696

    Article  PubMed  CAS  Google Scholar 

  32. Young MJ, Adams JE, Anderson GF, Boulton AJ, Cavanagh PR (1993) Medial arterial calcification in the feet of diabetic patients and matched non-diabetic control subjects. Diabetologia 36:615–621

    Article  PubMed  CAS  Google Scholar 

  33. Jeffcoate W (2004) Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link? Diabetologia 47:1488–1492

    Article  PubMed  CAS  Google Scholar 

  34. Chandra S, Rajamannan NM, Sucosky P (2012) Computational assessment of bicuspid aortic valve wall-shear stress: implications for calcific aortic valve disease. Biomech Model Mechanobiol 11:1085–1096

    Article  PubMed  Google Scholar 

  35. Brandenburg VM, Sinha S, Specht P, Ketteler M (2014) Calcific uraemic arteriolopathy: a rare disease with a potentially high impact on chronic kidney disease-mineral and bone disorder. Pediatr Nephrol. doi:10.1007/s00467-013-2746-7

    PubMed  Google Scholar 

  36. Hofmann Bowman MA, McNally EM (2012) Genetic pathways of vascular calcification. Trends Cardiovasc Med 22:93–98

    Article  PubMed  CAS  Google Scholar 

  37. St Hilaire C, Ziegler SG, Markello TC et al (2011) NT5E mutations and arterial calcifications. N Engl J Med 364:432–442

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Huang CC, Lloyd-Jones DM, Guo X et al (2011) Gene expression variation between African Americans and whites is associated with coronary artery calcification: the multiethnic study of atherosclerosis. Physiol Genomics 43:836–843

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Jude EB, Selby PL, Burgess J et al (2001) Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Diabetologia 44:2032–2037

    Article  PubMed  CAS  Google Scholar 

  40. Hessle L, Johnson KA, Anderson HC et al (2002) Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci U S A 99:9445–9449

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Acharya A, Hans CP, Koenig SN et al (2011) Inhibitory role of Notch1 in calcific aortic valve disease. PLoS One 6:e27743

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Garg V (2006) Molecular genetics of aortic valve disease. Curr Opin Cardiol 21:180–184

    Article  PubMed  Google Scholar 

  43. Shimizu T, Tanaka T, Iso T et al (2011) Notch signaling pathway enhances bone morphogenetic protein 2 (BMP2) responsiveness of Msx2 gene to induce osteogenic differentiation and mineralization of vascular smooth muscle cells. J Biol Chem 286:19138–19148

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Yun YS, Choi SJ, Lee JY et al (2014) Impact of arterial microcalcification of the vascular access on cardiovascular mortality in hemodialysis patients. Hemodial Int Int Symp Home Hemodial 18:54–61

    Article  Google Scholar 

  45. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942

    Article  PubMed  CAS  Google Scholar 

  46. Maldonado N, Kelly-Arnold A, Vengrenyuk Y et al (2012) A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture. Am J Physiol Heart Circ Physiol 303:H619–H628

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Nicoll R, Henein MY (2013) Arterial calcification: friend or foe? Int J Cardiol 167:322–327

    Article  PubMed  Google Scholar 

  48. Steinberg DI (2012) ACP Journal Club. Novel risk markers improved Framingham Risk Score cardiovascular event prediction in intermediate-risk adults. Ann Intern Med 157:JC6–JC13

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. Nelson RG, Gohdes DM, Everhart JE et al (1988) Lower-extremity amputations in NIDDM. 12-yr follow-up study in Pima Indians. Diabetes Care 11:8–16

    Article  PubMed  CAS  Google Scholar 

  51. Niskanen L, Siitonen O, Suhonen M, Uusitupa MI (1994) Medial artery calcification predicts cardiovascular mortality in patients with NIDDM. Diabetes Care 17:1252–1256

    Article  PubMed  CAS  Google Scholar 

  52. Carrington AL, Abbott CA, Griffiths J et al (2001) Peripheral vascular and nerve function associated with lower limb amputation in people with and without diabetes. Clin Sci 101:261–266

    Article  PubMed  CAS  Google Scholar 

  53. Alexander MY (2009) RANKL links arterial calcification with osteolysis. Circ Res 104:1032–1034

    Article  PubMed  CAS  Google Scholar 

  54. Mabilleau G, Petrova NL, Edmonds ME, Sabokbar A (2008) Increased osteoclastic activity in acute Charcot’s osteoarthropathy: the role of receptor activator of nuclear factor-κB ligand. Diabetologia 51:1035–1040

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Rogers LC, Frykberg RG, Armstrong DG et al (2011) The Charcot foot in diabetes. J Am Podiatr Med Assoc 101:437–446

    Article  PubMed  Google Scholar 

  56. Panizo S, Cardus A, Encinas M et al (2009) RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ Res 104:1041–1048

    Article  PubMed  CAS  Google Scholar 

  57. Olesen M, Skov V, Mechta M, Mumm BH, Rasmussen LM (2012) No influence of OPG and its ligands, RANKL and TRAIL, on proliferation and regulation of the calcification process in primary human vascular smooth muscle cells. Mol Cell Endocrinol 362:149–156

    Article  PubMed  CAS  Google Scholar 

  58. Byon CH, Sun Y, Chen J et al (2011) Runx2-upregulated receptor activator of nuclear factor κB ligand in calcifying smooth muscle cells promotes migration and osteoclastic differentiation of macrophages. Arterioscler Thromb Vasc Biol 31:1387–1396

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Browner WS, Lui LY, Cummings SR (2001) Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 86:631–637

    PubMed  CAS  Google Scholar 

  60. Jono S, Ikari Y, Shioi A et al (2002) Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 106:1192–1194

    Article  PubMed  CAS  Google Scholar 

  61. Collin-Osdoby P (2004) Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 95:1046–1057

    Article  PubMed  CAS  Google Scholar 

  62. Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H (2007) Vascular calcification and osteoporosis—from clinical observation towards molecular understanding. Osteoporos Int 18:251–259

    Article  PubMed  CAS  Google Scholar 

  63. Rasmussen LM, Tarnow L, Hansen TK, Parving HH, Flyvbjerg A (2006) Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients. Eur J Endocrinol Eur Fed Endocr Soc 154:75–81

    Article  CAS  Google Scholar 

  64. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  67. Kislinger T, Fu C, Huber B et al (1999) N ε-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740–31749

    Article  PubMed  CAS  Google Scholar 

  68. Ramasamy R, Yan SF, Schmidt AM (2009) RAGE: therapeutic target and biomarker of the inflammatory response—the evidence mounts. J Leukoc Biol 86:505–512

    Article  PubMed  CAS  Google Scholar 

  69. Ren X, Shao H, Wei Q, Sun Z, Liu N (2009) Advanced glycation end-products enhance calcification in vascular smooth muscle cells. J Int Med Res 37:847–854

    Article  PubMed  CAS  Google Scholar 

  70. Wang Z, Jiang Y, Liu N et al (2012) Advanced glycation end-product N ε-carboxymethyl-lysine accelerates progression of atherosclerotic calcification in diabetes. Atherosclerosis 221:387–396

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  72. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Manigrasso MB, Juranek J, Ramasamy R, Schmidt AM (2014) Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol Metab TEM 25:15–22

    Article  CAS  Google Scholar 

  74. Hermann A, Donato R, Weiger TM, Chazin WJ (2012) S100 calcium binding proteins and ion channels. Front Pharmacol 3:67

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sima AV, Botez GM, Stancu CS, Manea A, Raicu M, Simionescu M (2010) Effect of irreversibly glycated LDL in human vascular smooth muscle cells: lipid loading, oxidative and inflammatory stress. J Cell Mol Med 14:2790–2802

    Article  PubMed  CAS  Google Scholar 

  76. Donato R (2001) S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33:637–668

    Article  PubMed  CAS  Google Scholar 

  77. Tam XH, Shiu SW, Leng L, Bucala R, Betteridge DJ, Tan KC (2011) Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in type 2 diabetes. Clin Sci 120:81–89

    Article  PubMed  CAS  Google Scholar 

  78. Yan SF, Ramasamy R, Schmidt AM (2010) The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res 106:842–853

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. Cecil DL, Terkeltaub RA (2011) Arterial calcification is driven by RAGE in Enpp1-/- mice. J Vasc Res 48:227–235

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Hofmann Bowman MA, Gawdzik J, Bukhari U et al (2011) S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arterioscler Thromb Vasc Biol 31:337–344

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. 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 283:15319–15327

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Arumugam T, Ramachandran V, Gomez SB, Schmidt AM, Logsdon CD (2012) S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis. Clin Cancer Res Off J Am Assoc Cancer Res 18:4356–4364

    Article  CAS  Google Scholar 

  83. Towler DA (2011) Vascular calcification: it’s all the RAGE! Arterioscler Thromb Vasc Biol 31:237–239

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. Yoshida T, Flegler A, Kozlov A, Stern PH (2009) Direct inhibitory and indirect stimulatory effects of RAGE ligand S100 on sRANKL-induced osteoclastogenesis. J Cell Biochem 107:917–925

    Article  PubMed  CAS  Google Scholar 

  85. Franke S, Siggelkow H, Wolf G, Hein G (2007) Advanced glycation endproducts influence the mRNA expression of RAGE, RANKL and various osteoblastic genes in human osteoblasts. Arch Physiol Biochem 113:154–161

    Article  PubMed  CAS  Google Scholar 

  86. Chalk C, Benstead TJ, Moore F (2007) Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev (4), Art. no.: CD004572. doi:10.1002/14651858.CD004572.pub2

  87. Chang PC, Chong LY, Tsai SC, Lim LP (2014) Aminoguanidine inhibits the AGE–RAGE axis to modulate the induction of periodontitis but has limited effects on the progression and recovery of experimental periodontitis: a preliminary study. J Periodontol 85:729–739

    Article  PubMed  CAS  Google Scholar 

  88. Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ, McGill JB (2007) Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol 27:605–614

    Article  PubMed  CAS  Google Scholar 

  89. Witzke KA, Vinik AI, Grant LM et al (2011) Loss of RAGE defense: a cause of Charcot neuroarthropathy? Diabetes Care 34:1617–1621

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  90. Goova MT, Li J, Kislinger T et al (2001) Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. Am J Pathol 159:513–525

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  91. Wear-Maggitti K, Lee J, Conejero A, Schmidt AM, Grant R, Breitbart A (2004) Use of topical sRAGE in diabetic wounds increases neovascularization and granulation tissue formation. Ann Plast Surg 52:519–521, discussion 522

    Article  PubMed  Google Scholar 

  92. Lalla E, Lamster IB, Hofmann MA et al (2003) Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 23:1405–1411

    Article  PubMed  CAS  Google Scholar 

  93. Motyl K, McCabe LR (2009) Streptozotocin, type I diabetes severity and bone. Biol Proced Online 11:296–315

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  94. UK Prospective Diabetes Study (UKPDS) Group. (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

  95. Duckworth W, Abraira C, Moritz T et al (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360:129–139

    Article  PubMed  CAS  Google Scholar 

  96. Group AC, Patel A, MacMahon S et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572

    Article  PubMed  CAS  Google Scholar 

  97. Action to Control Cardiovascular Risk in Diabetes Study G, Gerstein HC, Miller ME et al (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559

    Article  PubMed  CAS  Google Scholar 

  98. Katakami N, Kaneto H, Shimomura I (2014) Carotid ultrasonography: a potent tool for better clinical practice in diagnosis of atherosclerosis in diabetic patients. J Diabetes Investig 5:3–13

    Article  PubMed  PubMed Central  Google Scholar 

  99. Polonsky TS, McClelland RL, Jorgensen NW et al (2010) Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA J Am Med Assoc 303:1610–1616

    Article  CAS  Google Scholar 

  100. Schurgin S, Rich S, Mazzone T (2001) Increased prevalence of significant coronary artery calcification in patients with diabetes. Diabetes Care 24:335–338

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We acknowledge support from the Manchester NIHR Biomedical Research Unit and Manchester Academic Health Science Centre (MAHSC).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

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All authors were responsible for the conception and design of the manuscript, drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.

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Authors and Affiliations

  1. Department of Medicine and Diabetes, Manchester Royal Infirmary, Manchester, UK

    Agbor Ndip & Andrew J. M. Boulton

  2. Department of Diabetes and Endocrinology, Warrington and Halton NHS Trust, Warrington, UK

    Agbor Ndip

  3. Centre for Endocrinology and Diabetes, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

    Agbor Ndip, Edward B. Jude & Andrew J. M. Boulton

  4. Manchester Diabetes Centre, 193, Hathersage Road, Manchester, M13 0JE, UK

    Agbor Ndip

  5. Healthcare Science Research Institute, Manchester Metropolitan University, Manchester, UK

    Fiona L. Wilkinson & M. Yvonne Alexander

  6. Department of Diabetes, Diabetes Centre, Tameside General Hospital, Ashton-Under-Lyne, UK

    Edward B. Jude

  7. Manchester Academic Health Science Centre, Manchester, UK

    Andrew J. M. Boulton & M. Yvonne Alexander

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  1. Agbor Ndip
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  2. Fiona L. Wilkinson
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Correspondence to Agbor Ndip.

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Agbor Ndip and Fiona L. Wilkinson are joint first authors.

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Ndip, A., Wilkinson, F.L., Jude, E.B. et al. RANKL–OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy. Diabetologia 57, 2251–2260 (2014). https://doi.org/10.1007/s00125-014-3348-z

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