The role of osteoprotegerin in cardiovascular disease

Annals of Medicine

Volumn 45, Issue 3, 2013, Pages 254-264

  Montagnana, Martina ^a   Lippi, Giuseppe ^b   Danese, Elisa ^a   Guidi, Gian Cesare ^a  

^a UNIVERSITY HOSPITAL OF VERONA   (Italy)

^b UNIVERSITY HOSPITAL OF PARMA   (Italy)

Author keywords

Atherosclerotic disease; Cardiovascular disease; Diabetes mellitus; Hypertension; OPG; Osteoprotegerin

Indexed keywords

APOLIPOPROTEIN B; BRAIN NATRIURETIC PEPTIDE; C REACTIVE PROTEIN; CELL ADHESION MOLECULE; CHOLESTEROL; CYTOKINE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INTERLEUKIN 1ALPHA; INTERLEUKIN 1BETA; LIPOPROTEIN A; LOSARTAN; N(G),N(G) DIMETHYLARGININE; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; PARATHYROID HORMONE; PLATELET DERIVED GROWTH FACTOR; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; TRIACYLGLYCEROL; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND;

ACUTE CORONARY SYNDROME; ACUTE HEART INFARCTION; AORTA VALVE STENOSIS; APOPTOSIS; ARTICLE; ATHEROGENESIS; ATHEROSCLEROSIS; ATHEROSCLEROTIC CARDIOVASCULAR DISEASE; CALCIFICATION; CARDIOVASCULAR DISEASE; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; CEREBROVASCULAR ACCIDENT; CORONARY ARTERY DISEASE; DIABETES MELLITUS; DIASTOLIC BLOOD PRESSURE; ENDOTHELIAL DYSFUNCTION; GLOMERULUS FILTRATION RATE; HEART FAILURE; HEART INFARCTION; HUMAN; HYPERLIPIDEMIA; HYPERTENSION; MORBIDITY; NONHUMAN; OSTEOCLAST; PATHOPHYSIOLOGY; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PREDICTIVE VALUE; PRIORITY JOURNAL; PROGNOSIS; PROTEIN BINDING; STABLE ANGINA PECTORIS; SYSTOLIC BLOOD PRESSURE; TUMOR CELL;

AGING; AORTIC DISEASES; ATHEROSCLEROSIS; BLOOD FLOW VELOCITY; BLOOD PRESSURE; CARDIOVASCULAR DISEASES; DIABETES MELLITUS; ENDOTHELIUM, VASCULAR; GENE EXPRESSION; HUMANS; INFLAMMATION; LIPIDS; OBESITY; OSTEOPROTEGERIN; POLYMORPHISM, GENETIC; PROGNOSIS; VASCULAR CALCIFICATION;

EID: 84876136816     PISSN: 07853890     EISSN: 13652060     Source Type: Journal    
DOI: 10.3109/07853890.2012.727019     Document Type: Article

References (139)

1. Proposed standard nomenclature for new tumor necrosis factor family members involved in the regulation of bone resorption: The American Society for Bone and Mineral Research President's Committee on Nomenclature. J Bone Miner Res. 2000; 15 : 2293-6.
2. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang M-S, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89 : 309-19. (Pubitemid 27199902)
3. Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun.; 234 : 137-42.
4. Tan KB, Harrop J, Reddy M, Young P, Terrett J, Emery J, et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene. 1997; 204 : 35-46. (Pubitemid 28022168)
5. Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteopro- tegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclas- togenesis in vitro. Endocrinology. 1998;139:1329-37. (Pubitemid 28510154)
6. Kwon BS, Wang S, Udagawa N, Haridas V, Lee ZH, Kim KK, et al. TR1, a new member of the tumor necrosis factor receptor family, induces fibroblast proliferation and inhibits osteoclastogenesis and bone resorption. FASEB J. 1998; 12 : 845-54. (Pubitemid 28294674)
7. Yun TJ, Chaudhary PM, Shu GL, Frazer JK, Ewings MK, Schwartz SM, et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol.; 161 : 6113-21.
8. Tintut Y, Demer L. Role of osteoprotegerin and its ligands and competing receptors in atherosclerotic calcification. J Investig Med. 2006;54:395-401. (Pubitemid 46123034)
9. Ziegler S, Kudlacek S, Luger A, Minar E. Osteoprotegerin plasma concentrations correlate with severity of peripheral artery disease. Atherosclerosis. 2005; 182 : 175-80. (Pubitemid 41188384)
10. Vik A, Mathiesen EB, Noto AT, Sveinbjornsson B, Brox J, Hansen JB. Serum osteoprotegerin is inversely associated with carotid plaque echogenicity in humans. Atherosclerosis. 2007; 191 : 128-34. (Pubitemid 46237632)
11. Collin-Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P. Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem. 2001;276:20659-72.
12. Secchiero P, Corallini F, Pandolfi A, Consoli A, Candido R, Fabris B, et al. An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction. Am J Pathol. 2006;169:2236-44. (Pubitemid 351181981)
13. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res. 2004; 95 : 1046-57. (Pubitemid 39557891)
14. Zauli G, Corallini F, Bossi F, Fischetti F, Durigutto P, Celeghini C, et al. Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo. Blood. 2007;110:536-43. (Pubitemid 47105391)
15. Sandberg WJ, Yndestad A, Oie E, Smith C, Ueland T, Ovchinnikova O, et al. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol. 2006;26:857-63. (Pubitemid 43732163)
16. Morinaga T, Nakagawa N, Yasuda H, Tsuda E, Higashio K. Cloning and characterization of the gene encoding human osteoprotegerin/osteo- clastogenesis-inhibitory factor. Eur J Biochem. 1998;254:685-91. (Pubitemid 28308123)
17. OPG. Available at: http://www.uniprot.org/uniprot/000300 (accessed 7 December 2011).
18. Yamaguchi K, Kinosaki M, Goto M, Kobayashi F, Tsuda E, Morinaga T, et al. Characterization of structural domains of human osteoclastogen- esis inhibitory factor. J Biol Chem. 1998;273:5117-23. (Pubitemid 28108672)
19. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999; 397 : 315-23.
20. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165-76. (Pubitemid 28180851)
21. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:490-5. (Pubitemid 38988958)
22. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3:673-82. (Pubitemid 26091143)
23. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA. 1999;96:3540-5. (Pubitemid 29168945)
24. LeBlanc HN, Ashkenazi A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 2003; 10 : 66-75. (Pubitemid 36511833)
25. Vitovski S, Phillips JS, Sayers J, Croucher PI. Investigating the interaction between osteoprotegerin and receptor activator of NF-kappaB or tumor necrosis factor-related apoptosis-inducing ligand: evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways. J Biol Chem. 2007;282:31601-9. (Pubitemid 350044899)
26. Ziolkowska M, Kurowska M, Radzikowska A, Luszczykiewicz G, Wiland P, Dziewczopolski W, et al. High levels of osteoprotegerin and soluble receptor activator of nuclear factor KB ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment. Arthritis Rheum. 2002;46:1744-53. (Pubitemid 34774505)
27. Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A, et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res. 1999; 14 : 518-27. (Pubitemid 29153384)
28. Chen D, Sarikaya NA, Gunn H, Martin SW, Young JD. ELISA method-ology for detection of modified osteoprotegerin in clinical studies. Clin Chem. 2001;47:747-9. (Pubitemid 32275821)
29. Chan BY, Buckley KA, Durham BH, Gallagher JA, Fraser WD. Effect of anticoagulants and storage temperature on the stability of receptor activator for nuclear factor-K B ligand and osteoprotegerin in plasma and serum. Clin Chem. 2003;49:2083-5. (Pubitemid 37449483)
30. Ndip A, Williams A, Jude EB, Serracino-Inglott F, Richardson S, Smyth JV, et al. The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic Charcot neuroarthropathy. Diabetes. 2011;60:2187-96.
31. Stern A, Laughlin GA, Bergstrom J, Barrett-Connor E. The sex-specific association of serum osteoprotegerin and receptor activator of nuclear factor KB legend with bone mineral density in older adults: the Rancho Bernardo study. Eur J Endocrinol. 2007;156:555-62. (Pubitemid 46796522)
32. Hofbauer LC, Heufelder AE. Role of receptor activator of nuclear factor-KB ligand and osteoprotegerin in bone cell biology. J Mol Med. 2001;79:243-53. (Pubitemid 32646379)
33. Hofbauer LC, Schoppet M. Osteoprotegerin gene polymorphism and the risk of osteoporosis and vascular disease. J Clin Endocrinol Metab. 2002; 87 : 4078-9.
34. Brändström H, Stiger F, Lind L, Kahan T, Melhus H, Kindmark A. A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function. Biochem Biophys Res Commun. 2002; 293 : 13-17. (Pubitemid 34694163)
35. Hofbauer LC, Shui C, Riggs BL, Dunstan CR, Speisberg TC, O'Brien T, et al. Effects of immunosuppressants on receptor activator of NF-KB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun. 2001;280:334-9. (Pubitemid 32917516)
36. Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an avβ3-induced, NF-KB-dependent survival factor for endothelial cells. J Biol Chem. 2000; 275 : 20959-62. (Pubitemid 30481782)
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 : 1610-6. (Pubitemid 34215580)
38. Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, et al. Serum osteopro- tegerin levels are associated with the presence and severity of coronary artery disease. Circulation. 2002;106:1192-4. (Pubitemid 34988634)
39. Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B, Hofbauer LC. Increased osteoprotegerin serum levels in men with coronary artery disease. J Clin Endocrinol Metab. 2003; 88 : 1024-8. (Pubitemid 36337751)
40. Browner WS, Lui LY, Cummings SR. Associations of serum osteopro- tegerin levels with diabetes, stroke, bone density, fractures and mortality in elderly women. J Clin Endocrinol Metab. 2001;86:631-7. (Pubitemid 32207471)
41. Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004; 109 : 2175-80. (Pubitemid 38625393)
42. Montecucco F, Steffens S, Mach F. Thie immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability? Clin Dev Immunol.; 2007 : 75805.
43. Abedin M, Tintut Y, Demer LL. Vascular calcifscation: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004; 24 : 1161-70. (Pubitemid 38880003)
44. Shaker OG, El-Shehaby A, Nabih M. Possible role of osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand as markers of plaque instability in coronary artery disease. Angiology. 2010;61:756-62.
45. Golledge J, McCann M, Mangan S, Lam A, Karan M. Osteoprotegerin and osteopontin are expressed at high concentrations within symptomatic carotid atherosclerosis. Stroke. 2004; 35 : 1636-41. (Pubitemid 38823639)
46. Bennett BJ, Scatena M, Kirk EA, Rattazzi M, Varon RM, Averill M, et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE mice-/-. Arterio- scler Thromb Vasc Biol. 2006; 26 : 2117-24. (Pubitemid 44253797)
47. Toffoli B, Pickering RJ, Tsorotes D, Wang B, Bernardi S, Kantharidis P, et al. Osteoprotegerin promotes vascular fibrosis via a TGF-β1 autocrine loop. Atherosclerosis. 2011;218:61-8.
48. Ovchinnikova O, Gylfe A, Bailey L, Nordstrom A, Rudling M, Jung C, et al. Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice - brief report. Arterioscler Thromb Vasc Biol. 2009; 29 : 1478-80.
49. Erdogan B, Aslan E, Bagis T, Gokcel A, Erkanli S, Bavbek M, et al.ntima-media thickness of the carotid arteries is related to serum osteoprotegerin levels in healthy postmenopausal women. Neurol Res. 2004; 26 : 658-61.
50. Siepi D, Marche si S, Vaudo G, Lupattelli G, Bagaglia F, Pirro M, et al. Preclinical vascular damage in white postmenopausal women: the relevance of osteoprotegerin. Metabolism. 2008; 57 : 321-5. (Pubitemid 351178720)
51. Vik A, Mathiesen EB, Brox J, Wilsgaard T, Nj0lstad I, j0rgensen L, et al. Relation between serum osteoprotegerin and carotid intima media thickness in a general population-the Troms0 Study. J Thromb Haemost. 2010; 8 : 2133-9.
52. Lieb W, Gona P, Larson MG, Massaro JM, Lipinska I, Keaney JF Jr, et al. Biomarkers of the osteoprotegerin pathway: clinical correlates, sub- clinical disease, incident cardiovascular disease, and mortality. Arte- rioscler Thromb Vasc Biol. 2010;30:1849-54.
53. Abedin M, Omland T, Ueland T, Khera A, Aukrust P, Murphy SA, et al. Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas Heart Study). Am J Cardiol. 2007;99 : 513-8. (Pubitemid 46215559)
54. Kurnatowska I, Grzelak P, Kaczmarska M, Stefanczyk L, Nowicki M. Serum osteoprotegerin is a predictor of progression of atherosclerosis and coronary calcification in hemodialysis patients. Nephron Clin Pract. 2011; 117:c297-304.
55. Semb AG, Ueland T, Aukrust P, Wareham NJ, Luben R, Gullestad L, et al. Osteoprotegerin and soluble receptor activator of nuclear factor- kappaB ligand and risk for coronary events: a nested case-control approach in the prospective EPIC-Norfolk population study 1993-2003. Arterioscler Thromb Vasc Biol. 2009; 29 : 975-80.
56. Vik A, Mathiesen EB, Brox J, Wilsgaard T, Nj0lstad I, j0rgensen L, et al. Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Troms0 Study. J Thromb Haemost. 2011;9:638-44.
57. Ueland T, Wilson SG, Amirul Islam FM, Mullin B, Devine A, Bollerslev J, et al. A cohort study of the effects of serum osteoprotegerin and osteoprotegerin gene polymorphisms on cardiovascular mortality in elderly women. Clin Endocrinol (Oxf). 2009; 71 : 828-33.
58. Pedersen ER, Ueland T, Seifert R, Aukrust P, Schartum-Hansen H, Ebbing M, et al. Serum osteoprotegerin levels and long-term prognosis in patients with stable angina pectoris. Atherosclerosis. 2010;212:644-9.
59. Jono S, Otsuki S, Higashikuni Y, Shioi A, Mori ?, Hara K, et al. Serum osteoprotegerin levels and long-term prognosis in subjects with stable coronary artery disease. J Thromb Haemost. 2010;8:1170-5.
60. Ueland T, Jemtland R, Godang K, Kjekshus J, Hognestad A, Omland T, et al. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol. 2004;44:1970-6. (Pubitemid 39473280)
61. Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, et al. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol.; 51 : 627-33.
62. Yang Q, Lu S, Chen Y, Song X, Jin Z, Yuan F, et al. Plasma osteoprote- gerin levels and long-term prognosis in patients with intermediate coronary artery lesions. Clin Cardiol. 2011;34:447-53.
63. Ohmori R, Momiyama Y, Taniguchi H, Kihara T, Tanaka N, Kato R, et al. Association between osteoprotegerin gene polymorphism and coronary artery disease in Japanese men. Atherosclerosis. 2006; 187 : 215-7. (Pubitemid 43817020)
64. Soufi M, Schoppet M, Sattler AM, Herzum M, Maisch B, Hofoauer LC, et al. Osteoprotegerin gene polymorphisms in men with coronary artery disease. J Clin Endocrinol Metab. 2004; 89 : 3764-8. (Pubitemid 39071469)
65. Mogelvang R, Pedersen SH, Flyvbjerg A, B j erre M, Iversen AZ, Galatius S, et al. Comparison of osteoprotegerin to traditional atherosclerotic risk factors and high-sensitivity C-reactive protein for diagnosis of atherosclerosis. Am J Cardiol. 2012;109:515-20.
66. Ren MY, Sui SJ, Zhang Y, Xu FY, Xu XQ, Zhao JJ, et al. Increased plasma osteoprotegerin levels are associated with the presence and severity of acute coronary syndrome. Acta Cardiol. 2008; 63 : 615-22.
67. O'Sullivan EP, Ashley DT, Davenport C, Kelly J, Devlin N, Crowley R, et al. Osteoprotegerin is higher in peripheral arterial disease regardless of glycaemic status. Thromb Res. 2010;126:e423-7.
68. Ali Z, Ellington AA, Mosley TH Jr, Kullo IJ. Association of serum osteoprotegerin with ankle-brachial index and urine albumin: creatinine ratio in African-Americans and non-Hispanic whites. Atherosclerosis. 2009; 206 : 575-80.
69. Helske S, Kovanen PT, Lindstedt K A, Salmela K, Lommi J, Turto H, et al. Increased circulating concentrations and augmented myocardial extraction of osteoprotegerin in heart failure due to left ventricular pressure overload. Eur J Heart Fail. 2007; 9 : 357-63. (Pubitemid 46441975)
70. Ueland T, Dahl CP, Kjekshus J, Hulthe J, Böhm M, Mach F, et al. Oste- oprotegerin predicts progression of chronic heart failure: results from CORONA. Circ Heart Fail. 2011;4:145-52.
71. Johnson RC, Leopold JA, Loscalzo J. Vascular calcifscation: pathobiologi- cal mechanisms and clinical implications. Circ Res. 2006;99:1044-59. (Pubitemid 44729928)
72. Sennels HP, Jacobsen S, Jensen T, Hansen MS, Ostergaard M, Nielsen HJ, et al. Biological variation and reference intervals for circulating osteopontin, osteoprotegerin, total soluble receptor activator of nuclear factor kappa B ligand and high-sensitivity C-reactive protein. Scand J Clin Lab Invest. 2007;67:821-35. (Pubitemid 350158770)
73. Jung K, Lein M, Hosslin K, Grosse A, Roth S, Possinger K, et al. Oste- oprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) in the serum of healthy adults. Int J Biol Markers. 2002; 3: 177-81. (Pubitemid 35370061)
74. Jensen JK, Ueland T, Atar D, Gullestad L, Mickley H, Aukrust P, et al. Osteoprotegerin concentrations and prognosis in acute ischaemic stroke. J Intern Med. 2010; 267 : 410-7.
75. Terekeci HM, Senol MG, Top C, Sahan B, Celik S, Sayan O, et al. Plasma osteoprotegerin concentrations in type 2 diabetic patients and its association with neuropathy. Exp Clin Endocrinol Diabetes. 2009;117: 119-23.
76. Kudlacek S, Schneider B, Woloszczuk W, Pietschmann P, Willvonseder R. Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone. 2003;6:681-6. (Pubitemid 37303940)
77. Khosla S, Arrighi HM, Melton LJ, Atkinson EJ, O'Fallon WM, Dunstan C, et al. Correlates of osteoprotegerin levels in women and men. Osteoporos Int. 2002;13:394-9. (Pubitemid 34625396)
78. Szulc P, Hofbauer LC, Heufelder AE, Roth S, Delmas PD. Osteoprote- gerin serum levels in men: correlation with age, estrogen, and testosterone status. J Clin Endocrinol Metab. 2001;86:3162-5. (Pubitemid 32673481)
79. Holecki M, Zahorska-Markiewicz B, Janowska J, Nieszporek T, Wojaczynska-Stanek K, Zak-Golab A, et al. The influence of weight loss on serum osteoprotegerin concentration in obese perimenopausal women. Obesity (Silver Spring). 2007; 15 : 1925-9. (Pubitemid 47402223)
80. Ashley DT, O'Sullivan EP, Davenport ?, Devlin N, Crowley RK, McCaffrey N, et al. Similar to adiponectin, serum levels of osteopro- tegerin are associated with obesity in healthy subjects. Metabolism. 2011;60:994-1000.
81. Gannagé-Yared MH, Yaghi C, Habre B, Khalife S, Noun R, Germanos-Haddad M, et al. Osteoprotegerin in relation to body weight, lipid parameters insulin sensitivity, adipocytokines, and C-reactive protein in obese and non-obese young individuals: results from both crosssectional and interventional study. Eur J Endocrinol. 2008;158:353-9. (Pubitemid 351405000)
82. Wasilewska A, Rybi-Szuminska A A, Zoch-Zwier z W. Serum osteopro- tegrin (OPG) and receptor activator of nuclear factor kappaB (RANKL) in healthy children and adolescents. J Pediatr Endocrinol Metab. 2009;22:1099-104.
83. Kim SM, Lee J, Ryu OH, Lee KW, Kim HY, Seo JA, et al. Serum osteo- protegerin levels are associated with inflammation and pulse wave velocity. Clin Endocrinol (Oxf). 2005; 63 : 594-8. (Pubitemid 41626757)
84. Stçpien E, Wypasek E, Stopyra K, Konieczynska M, Przybylo M, Pasowicz M. Increased levels of bone remodeling biomarkers (osteoprotegerin and osteopontin) in hypertensive individuals. Clin Biochem. 2011;44:826-31.
85. Rhee EJ, Lee WY, Kim SY, Kim BJ, Sung , Kim BS, et al. Relationship of serum osteoprotegerin levels with coronary artery disease severity, left ventricular hypertrophy and C-reactive protein. Clin Sci (Lond). 2005; 108 : 237-43.
86. Xiang GD, Sun HL, Zhao LS, Hou J, Yue L, Xu L. [Changes of osteo- protegerin before and after insulin therapy in type 1 diabetic patients]. Zhonghua Yi Xue Za Zhi. 2007; 87 : 1234-7. (Pubitemid 47073168)
87. Xiang GD, Xu L, Zhao LS, Yue L, Hou J. Thie relationship between plasma osteoprotegerin and endothelium-dependent arterial dilation in type 2 diabetes. Diabetes. 2006;55:2126-31. (Pubitemid 44509988)
88. Gannagé -Yared MH, Fares F, Semaan M, Khalife S, Jambart S. Circulating osteoprotegerin is correlated with lipid profile, insulin sensitivity, adiponectin and sex steroids in an ageing male population. Clin Endocrinol (Oxf). 2006; 64 : 652-8. (Pubitemid 43775003)
89. Vik A, Mathiesen EB, Johnsen SH, Brox J, Wilsgaard T, Njolstad I, et al. Serum osteoprotegerin, sRANKL and carotid plaque formation and growth in a general population-the Troms0 study. J Thromb Haemost. 2010; 8 : 898-905.
90. O'Sullivan EP, Ashley DT, Davenport C, Devlin N, Crowley R, Agha A, et al. Osteoprotegerin and biomarkers of vascular inflammation in type 2 diabetes. Diabetes Metab Res Rev. 2010;26:496-502.
91. Pepene CE, Ilie IR, Marian I, Duncea I. Circulating osteoprotegerin and soluble receptor activator of nuclear factor KB ligand in polycystic ovary syndrome: relationships to insulin resistance and endothelial dysfunction. Eur J Endocrinol. 2011;164:61-8.
92. Golledge J, Leicht AS, Crowther RG, Glanville S, Clancy P, Sangla KS, et al. Determinants of endothelial function in a cohort of patients with peripheral artery disease. Cardiology. 2008; 111 : 51-6.
93. Boneti PO, Lerman LO, Lerman A. Endothelial dysfunction, a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003; 23 : 168-75. (Pubitemid 36231924)
94. Shin JY, Shin YG, Chung CH. Elevated serum osteoprotegerin levels are associated with vascular endothelial dysfunction in type 2 diabetes. Diabetes Care. 2006;29:1664-6.
95. Xiang GD, Pu JH, Zhao LS, Sun HL, Hou J, Yue L. Association between plasma osteoprotegerin concentrations and urinary albumin excretion in Type 2 diabetes. Diabet Med. 2009; 26 : 397-403.
96. Tsioufis C, Aggelis A, Dimitriadis K, Thomopoulos C, Kasiakogias A, Tzamou V, et al. Relationships of osteoprotegerin with albuminuria and asymmetric dimethylarginine in essential hypertension: integrating vascular dysfunction. Expert Opin Ther Targets. 2011;15:1347-53.
97. Blazquez-Medela AM, Garcia-Ortiz L, Gómez-Marcos MA, Recio-Rodriguez JI, Sanchez-Rodriguez A, López-Novoa JM, et al. Osteoprotegerin is associated with cardiovascular risk in hypertension and/or diabetes. Eur J Clin Invest. 2012;42:548-56.
98. Zagura M, Serg M, Kampus P, Zilmer M, Zilmer K, Eha J, et al. Association of osteoprotegerin with aortic stiffness in patients with symptomatic peripheral artery disease and in healthy subjects. Am J Hypertens. 2010; 23 : 586-91.
99. Akinci B, Demir T, Celtik A, Baris M, Yener S, Ozcan MA, et al. Serum osteoprotegerin is associated with carotid intima media thickness in women with previous gestational diabetes. Diabetes Res Clin Pract. 2008; 82 : 172-8.
100. Schoppet M, Al Fakhri N, Franke FE, Katz N, Barth PJ, Maisch B, et al. Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor- kappaB ligand in Monckeberg's sclerosis and atherosclerosis. J Clin Endocrinol Metab. 2004;89 : 4104-12. (Pubitemid 39071519)
101. Mangan SH, Van Campenhout A, Rush C, Golledge J. Osteoprotegerin upregulates endothelial cell adhesion molecule response to tumor necrosis factor-alpha associated with induction of angiopoietin-2. Cardiovasc Res. 2007; 76 : 494-505. (Pubitemid 350007458)
102. Olesen P, Ledet T, Rasmussen LM. Arterial osteoprotegerin: increased amounts in diabetes and modifiable synthesis from vascular smooth muscle cells by insulin and TNF-alpha. Diabetologia. 2005;48:561-8. (Pubitemid 40487304)
103. Kim HH, Shin HS, Kwak HJ, Ahn KY, Kim JH, Lee HJ, et al. RANKL regulates endothelial cell survival through the phosphatidylinositol 3'- kinase/Akt signal transduction pathway. FASEB J. 2003; 17 : 2163-5.
104. Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, et al. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Lett. 2002;521:180-4. (Pubitemid 34628481)
105. Knudsen ST, Foss CH, Poulsen PL, Andersen NH, Mogensen CE, Rasmussen LM. Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications. Eur J Endocrinol. 2003; 149 : 39-42. (Pubitemid 36874202)
106. Chen WJ, Rijzewijk LJ, van der Meer RW, Heymans MW, van Duinkerken E, Lubberink M, et al. Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men. Cardiovasc Diabetol. 2011; 10 : 67.
107. Rasmussen LM, Ledet T. Osteoprotegerin and diabetic macroangiopathy. Horm Metab Res. 2005;37(Suppl 1):90-4.
108. Jorsal A, Tarnow L, Flyvbjerg A, Parving HH, Rossing P, Rasmussen LM. Plasma osteoprotegerin levels predict cardiovascular and all-cause mortality and deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetologia. 2008; 51 : 2100-7.
109. Yaturu S, Rains J, Jain SK. Relationship of elevated osteoprotegerin with insulin resistance, CRP, and TNF-alpha levels in men with type 2 diabetes. Cytokine. 2008;44:168-71.
110. Altinova AE, Toruner F, Akturk M, Bukan N, Yetkin I, Cakir N, et al. Relationship between serum osteoprotegerin, glycemic control, renal function and markers of atherosclerosis in type 2 diabetes. Scand J Clin Lab Invest. 2011;71:340-3.
111. Reinhard H, Lajer M, Gall MA, Tarnow L, Parving HH, Rasmussen LM, et al. Osteoprotegerin and mortality in type 2 diabetic patients. Diabetes Care. 2010; 33 : 2561-6.
112. Anand DV, Lahiri A, Lim E, Hopkins D, Corder R. Thie relationship between plasma osteoprotegerin levels and coronary artery calcification in uncomplicated type-2 diabetic subjects. Am Coll Cardiol. 2006;47:1850-7.
113. Avignon A, Sultan A, Piot C, Elaerts S, Cristol JP, Dupuy AM. Osteo- protegerin is associated with silent coronary artery disease in high-risk but asymptomatic type 2 diabetic patients. Diabetes Care. 2005; 28: 2176-80. (Pubitemid 41242464)
114. Xiang GD, Sun HL, Zhao LS. Changes of osteoprotegerin before and after insulin therapy in type I diabetic patients. Diabetes Res Clin Pract. 2007;76:199-206.
115. Park JS, Cho MH, Nam JS, Yoo JS, Ahn CW, Cha BS, et al. Effect of pioglitazone on serum concentrations of osteoprotegerin in patients with type 2 diabetes mellitus. Eur J Endocrinol. 2011;164:69-74.
116. Nybo M, Preil SR, Juhl HF, Olesen M, Yderstraede K, Gram J, et al. Rosiglitazone decreases plasma levels of osteoprotegerin in a randomized clinical trial with type 2 diabetes patients. Basic Clin Pharmacol Toxicol. 2011;109:481-5.
117. Singh DK, Winocour P, Summerhayes B, Viljoen A, Sivakumar G, Farrington K. Low serum osteoprotegerin levels in normoalbuminuric type 1 diabetes mellitus. Acta Diabetol. 2010;47(Suppl 1):105-10.
118. Rasmussen LM, Tarnow L, Hansen TK, Parving HH, Flyvbjerg A. Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients. Eur J Endocrinol. 2006;154:75-81. (Pubitemid 43250739)
119. Uemura H, Yasui T, Miyatani Y, Yamada M, Hiyoshi M, Arisawa K, et al. Circulating osteoprotegerin is associated with age and systolic blood pressure, but not with lipid profile or fasting glucose, in postmenopausal women. Menopause. 2008; 15 : 180-4.
120. Khattar RS, Swales JD, Dore ?, Senior R, Lahiri A. Eiïect of aging on the prognostic significance of ambulatory systolic, diastolic, and pulse pressure in essential hypertension. Circulation. 2001;104:783-9. (Pubitemid 32762676)
121. Noheria A, Mosley TH Jr, Kullo IJ. Association of serum osteoprote- gerin with left ventricular mass in African American adults with hypertension. Am J Hypertens. 2010; 23 : 767-74.
122. Omland T, Drazner MH, Ueland T, Abedin M, Murphy SA, Aukrust P, et al. Plasma osteoprotegerin levels in the general population: relation to indices of left ventricular structure and function. Hypertension. 2007;49:1392-8. (Pubitemid 46809385)
123. Brändström H, Stiger F, Kahan T, Melhus H, Nyström F, Höman KP, et al. A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients. The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA). Blood Press. 2004;13:152-7. (Pubitemid 38967758)
124. Messika-Zeitoun D, Bielak LF, Peyser PA, Sheedy PF, Turner ST, Nkomo VT, et al. Aortic valve calcification: determinants and progres-sion in the population. Arterioscler Vasc Thromb Biol. 2007; 27 : 642-8.
125. O'Brien KD. Pathogenesis of calcifsc aortic valve disease: a disease process comes of age (and a good deal more). Arterioscler Thromb Vasc Biol. 2006; 26 : 1721-8. (Pubitemid 44305324)
126. Doherty TM, Asotra K, Fitzpatrick LA, Qiao JH, Wilkin DJ, Detrano RC, et al. Calcifscation in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci USA. 2003;100:11201-6. (Pubitemid 37205912)
127. Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoc A, Kilic R, et al. Receptor activator of nuclear factor kappaB ligand and osteopro- tegerin regulate aortic valve calcification. J Mol Cell Cardiol. 2004; 36 : 57-66. (Pubitemid 38084791)
128. Adamczyk T, Mizia-Stec K, Mizia M, Haberka M, Chmiel A, Chudek J, et al. Biomarkers of calcification and atherosclerosis in patients with degenerative aortic stenosis in relation to concomitant coronary artery disease. Pol Arch Med Wewn. 2012; 122 : 14-21.
129. Ueland T, Aukrust P, Dahl CP, Husebye T, Solberg OG, T0nnessen T, et al. Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis. J Intern Med. 2011;270:452-60.
130. Quercioli A, Montecucco F, Bertolotto M, Ottonello L, Pende A, Mach F, et al. Coronary artery calcification and cardiovascular risk: the role of RANKL/OPG signalling. Eur J Clin Invest. 2010;40:645-54.
131. Quercioli A, Luciano Viviani G, Dallegri F, Mach F, Montecucco F. Receptor activator of nuclear factor kappa B ligand/osteoprotegerin pathway is a promising target to reduce atherosclerotic plaque calcification. Crit Pathw Cardiol. 2010;9:227-30.
132. Vega D, Maalouf NM, Sakhaee K. CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/ osteoprotegerin: clinical
133. Baud'huin M, Lamoureux F, Duplomb L, Rédini F, Heymann D. RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases. Cell Mol Life Sci. 2007;64:2334-50. (Pubitemid 47402577)
134. Body J-J, Greipp P, Coleman RE, Façon T, Geurs F, Fermand J-P, et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer. 2003; 97 : 887-92. (Pubitemid 36125828)
135. Weiner LM. Fully human therapeutic monoclonal antibodies. J Immu- nother. 1997; 29 : 1-9.
136. Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol. 2005;5: 618-25. (Pubitemid 41614462)
137. Sinningen K, Tsourdi E, Rauner M, Rachner TD, Hamann ?, Hofoauer LC. Skeletal and extraskeletal actions of denosumab. Endocrine. 2012;42:52-62.
138. Kadoglou NP, Sailer N, Moumtzouoglou A, Kapelouzou A, Gerasimidis T, Liapis CD. Aggressive lipid-lowering is more effective than moderate lipid-lowering treatment in carotid plaque stabilization. J Vasc Surg. 2010;51:114-21.
139. Kadoglou NP, Gerasimidis T, Moumtzouoglou A, Kapelouzou A, Sailer N, Fotiadis G, et al. Intensive lipid-lowering therapy ameliorates novel calcification markers and GSM score in patients with carotid stenosis. Eur J Vasc Endovasc Surg. 2008;35:661-8. (Pubitemid 351680152)