Osteoprotegerin: A Biomarker With Many Faces

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 30, No. 9Osteoprotegerin: A Biomarker With Many Faces Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBOsteoprotegerin: A Biomarker With Many Faces Kenneth Caidahl, Thor Ueland and Pål Aukrust Kenneth CaidahlKenneth Caidahl From the Department of Clinical Physiology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden (K.C.); Research Institute for Internal Medicine (T.U., P.A.), Section of Clinical Immunology and Infectious Diseases (P.A.), Department of Endocrinology, Oslo University Hospital Rikshospitalet (T.U.), and Faculty of Medicine, University of Oslo (P.A.), Oslo, Norway. Search for more papers by this author , Thor UelandThor Ueland From the Department of Clinical Physiology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden (K.C.); Research Institute for Internal Medicine (T.U., P.A.), Section of Clinical Immunology and Infectious Diseases (P.A.), Department of Endocrinology, Oslo University Hospital Rikshospitalet (T.U.), and Faculty of Medicine, University of Oslo (P.A.), Oslo, Norway. Search for more papers by this author and Pål AukrustPål Aukrust From the Department of Clinical Physiology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden (K.C.); Research Institute for Internal Medicine (T.U., P.A.), Section of Clinical Immunology and Infectious Diseases (P.A.), Department of Endocrinology, Oslo University Hospital Rikshospitalet (T.U.), and Faculty of Medicine, University of Oslo (P.A.), Oslo, Norway. Search for more papers by this author Originally published1 Sep 2010https://doi.org/10.1161/ATVBAHA.110.208843Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:1684–1686Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is a soluble decoy receptor for the osteoclast differentiation factor receptor-activator of nuclear factor κB ligand (RANKL) that inhibits interaction between RANKL and its membrane-bound receptor RANK (Figure).1 The RANKL/OPG/RANK axis has been shown to regulate bone remodeling2,3 and was more recently found to be involved in carcinogenesis as well as central thermoregulation.4,5 This system has also been linked to the development of atherosclerosis and plaque destabilization.6,7 RANKL exhibits several properties with relevance to atherogenesis, such as promotion of inflammatory responses in T cells and dendritic cells, induction of chemotactic properties in monocytes, induction of matrix metalloproteinase (MMP) activity in vascular smooth muscle cells (SMC), and RANKL has also been found to have prothrombotic properties.2,8 In observational studies, elevated circulating OPG levels have been associated with prevalence and severity of coronary artery disease, cerebrovascular disease, and peripheral vascular disease.2,8 Circulating OPG levels are increased in patients with acute coronary syndrome,9 and enhanced expression has been found within symptomatic carotid plaques.10 Elevated OPG levels have also been associated with the degree of coronary calcification in the general population as a marker of coronary atherosclerosis.11 OPG has been reported to predict survival in patients with heart failure after acute myocardial infarction,12 to predict heart failure hospitalization and mortality in patients with acute coronary syndrome,9 and to be associated with long-term mortality in patients with ischemic stroke.13 There are also a few studies that show a relationship between OPG and cardiovascular disease (CVD) and related mortality in the general population.6,14Download figureDownload PowerPointFigure. A, Regulation of osteoclastogensesis by the RANKL/OPG/RANK axis. Soluble and membrane bound RANKL on osteoblasts stimulate: proliferation into preosteoclasts (1), differentiation to become prefusion osteoclasts (2), fusion into multinucleated bone resorbing osteoclasts (3), and prevent apoptosis of mature osteoclasts (4). OPG blocks the effects of RANKL by neutralizing and preventing binding to its receptor RANK. B, Sources of RANKL in the vessel wall. Proinflammatory cytokines upregulate soluble or membrane-bound RANKL on: endothelial cells (1), activated T cells (2), vascular SMCs undergoing osteogenic differentiation (3), and endothelial cells in contact with CD-44 expressing vascular SMC (4). C, Function of RANKL in atherosclerotic vascular calcification. RANKL may play a role in the atherosclerotic process through: triggering endothelial cells survival and proliferation (1), stimulating monocyte and lymphocyte transmigration and activation of T cells (2), maturation and activation of dendritic cells (3), increased matrix MMP activity from monocytes and vascular SMC that may promote plaque rupture and thrombus formation (4), and promotion of osteogenesis, leading to synthesis of bone proteins and matrix calcification within the arterial vessel (5).See accompanying article on page 1849In this issue, Lieb et al15 describe the clinical correlates, from subclinical disease to mortality, of serum OPG in 3250 Framingham study participants. They found that OPG was related to risk factors, such as age, smoking, diabetes, systolic blood pressure, and prevalent CVD, as well as CVD-related mortality. There was also a (nonsignificant) relation between OPG and coronary calcification, and the Dallas heart study demonstrated a relation of OPG to coronary as well as aortic calcifications.11 In addition, Vik et al16 have recently shown that OPG was an independent predictor of plaque growth in the general population in women but not in men, indicating gender-specific actions of OPG in plaque progression. Taken together, all these studies suggest that OPG may be a new promising marker for risk prediction in CVD.On the other hand, although the pathogenic effects of the RANKL/OPG/RANK axis in atherogenesis has been related to RANKL activities (Figure), Lieb et al did not find any relation between serum levels of RANKL and CVD, which is in line with the EPIC-Norfolk and the Tromsø studies14,16 but not with the Bruneck study.6 Moreover, genetic OPG inactivation accelerates advanced atherosclerotic lesion progression in older apolipoprotein E−/− mice, and OPG treatment promotes SMC accumulation, collagen fiber formation, and development of fibrous caps in apolipoprotein E deficient mice, suggesting a protective rather than harmful effect of OPG in atherogenesis.8,17 The reasons for these apparently discrepant findings are at present not clear, but several potential explanations may exist. A reliable biomarker in CVD is not necessarily an important mediator in atherosclerosis but rather a stable marker of up-stream pathways that are involved in the pathogenesis of CVD. In fact, the leading role of C-reactive protein as an inflammatory biomarker in CVD is not primarily based on its pathogenic role in these disorders but rather on its ability to reflect upstream inflammatory activity. OPG has been shown to be modulated by various up-stream inflammatory mediators, such as interleukin 1 and tumor necrosis factor α.18 Moreover, because OPG circulates at much higher levels than RANKL, it may be a more stable overall measure of RANKL/RANK activity than soluble RANKL. Therefore, the role of OPG as a marker in CVD may not be related to its role as a mediator but reflect its role as a stable marker of activity in the RANKL/OPG/RANK axis, as well as the activities in inflammatory pathways that are involved in atherogenesis. Thus, mirroring several interaction pathways with relevance to atherosclerosis, such as inflammation, matrix degradation, and vascular calcification. Moreover, Golledge et al10 reported OPG to be expressed at higher levels in symptomatic carotid plaques than in asymptomatic carotid plaques, and it is possible that the relation between circulating OPG levels and CVD may, at least in part, reflect shedding from atherosclerotic lesions. However, several questions remain unresolved. First, although OPG is a known inhibitor of RANKL, its biological effect may depend on the molar ratio between RANKL and OPG.7 Thus, although OPG under low RANKL/OPG ratios attenuates RANKL-mediated effects, it has during high RANKL/OPG ratios been found to enhance the RANKL-mediated effects on MMP levels in vascular SMC. Also, OPG has been shown to exert chemotactic properties, and SMC incubated with OPG develop impaired cell proliferation, increased apoptosis, increased MMP-2 and MMP-9 levels, and enhanced interleukin 6 production.19 Furthermore, in addition to its ability to bind RANKL, OPG seems to also bind tumor necrosis factor-related apoptosis inducing ligand,20 but the role of this interaction, with potential antiapoptotic net effects, in atherogenesis has not been studied. Second, in line with some other studies, Lieb et al found an inverse correlation between circulating RANKL and OPG levels. It is important to clarify if OPG and RANKL are differently regulated or if these findings merely reflect enhanced binding of circulating RANKL to OPG in excess of OPG, leading to decreased levels of free RANKL. Moreover, although several studies have suggested a role for RANKL/OPG/RANK axis in atherogenesis, OPG was recently found to inhibit vascular calcification without affecting atherosclerosis in low-density lipoprotein receptor-deficient mice.21 In the Tromsø study, OPG was associated with plaque progression but not with novel plaque formation, suggesting a restricted role in atherogenesis.16 Furthermore, drugs targeting the RANKL/OPG/RANK axis have not been related to CVD events in randomized trials,22,23 but importantly, these studies were not designed to evaluate their effect on CVD.Although several studies suggest the involvement of RANKL/OPG/RANK axis in coronary artery disease and related atherosclerotic disorders,18,24 more evidence is needed to evaluate the predictive and diagnostic value of serum OPG levels for clinical use as well as the pathogenic importance of these mediators in the process of atherosclerosis and plaque rupture.Sources of FundingThis work was supported by the Swedish Research Council and the Swedish Heart Lung foundation (K.C.).DisclosuresNone.FootnotesCorrespondence to Kenneth Caidahl, MD, PhD, Department of Clinical Physiology N2:01, Karolinska University Hospital, SE 171 76 Stockholm, Sweden. E-mail [email protected] References 1 Schoppet M, Preissner KT, Hofbauer LC. Rank ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol. 2002; 22: 549–553.LinkGoogle Scholar2 Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between rankl and ifn-γ. Nature. 2000; 408: 600–605.CrossrefMedlineGoogle Scholar3 Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, Mumm S. Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med. 2002; 347: 175–184.CrossrefMedlineGoogle Scholar4 Hanada R, Leibbrandt A, Hanada T, Kitaoka S, Furuyashiki T, Fujihara H, Trichereau J, Paolino M, Qadri F, Plehm R, Klaere S, Komnenovic V, Mimata H, Yoshimatsu H, Takahashi N, von Haeseler A, Bader M, Kilic SS, Ueta Y, Pifl C, Narumiya S, Penninger JM. Central control of fever and female body temperature by rankl/rank. Nature. 2009; 462: 505–509.CrossrefMedlineGoogle Scholar5 Mikami S, Katsube K, Oya M, Ishida M, Kosaka T, Mizuno R, Mochizuki S, Ikeda T, Mukai M, Okada Y. Increased rankl expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol. 2009; 218: 530–539.CrossrefMedlineGoogle Scholar6 Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, Santer P, Smolen J, Poewe W, Willeit J. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004; 109: 2175–2180.LinkGoogle Scholar7 Sandberg WJ, Yndestad A, Oie E, Smith C, Ueland T, Ovchinnikova O, Robertson AK, Muller F, Semb AG, Scholz H, Andreassen AK, Gullestad L, Damas JK, Froland SS, Hansson GK, Halvorsen B, Aukrust P. Enhanced t-cell expression of rank ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol. 2006; 26: 857–863.LinkGoogle Scholar8 Bennett BJ, Scatena M, Kirk EA, Rattazzi M, Varon RM, Averill M, Schwartz SM, Giachelli CM, Rosenfeld ME. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older apoe−/− mice. Arterioscler Thromb Vasc Biol. 2006; 26: 2117–2124.LinkGoogle Scholar9 Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, Herlitz J, Aukrust P, Hartford M, Caidahl K. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol. 2008; 51: 627–633.CrossrefMedlineGoogle Scholar10 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: 1636–1641.LinkGoogle Scholar11 Abedin M, Omland T, Ueland T, Khera A, Aukrust P, Murphy SA, Jain T, Gruntmanis U, McGuire DK, de Lemos JA. Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas heart study). Am J Cardiol. 2007; 99: 513–518.CrossrefMedlineGoogle Scholar12 Ueland T, Kjekshus J, Froland SS, Omland T, Squire IB, Gullestad L, Dickstein K, Aukrust P. Plasma levels of soluble tumor necrosis factor receptor type i during the acute phase following complicated myocardial infarction predicts survival in high-risk patients. J Am Coll Cardiol. 2005; 46: 2018–2021.CrossrefMedlineGoogle Scholar13 Jensen JK, Ueland T, Atar D, Gullestad L, Mickley H, Aukrust P, Januzzi JL. Osteoprotegerin concentrations and prognosis in acute ischaemic stroke. J Intern Med. 2010; 267: 410–417.CrossrefMedlineGoogle Scholar14 Semb AG, Ueland T, Aukrust P, Wareham NJ, Luben R, Gullestad L, Kastelein JJ, Khaw KT, Boekholdt SM. 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: 975–980.LinkGoogle Scholar15 Lieb W, Gona P, Larson MG, Massaro JM, Lipinska I, Keaney JF Jr, Rong J, Corey D, Hoffmann U, Fox CS, Vasan RS, Benjamin EJ, O'Donnell CJ, Kathiresan S. Biomarkers of the osteoprotegerin pathway. Clinical correlates, subclinical disease, incident cardiovascular disease, and mortality. Arterioscler Thromb Vasc Biol. 2010; 30: 1849–1854.LinkGoogle Scholar16 Vik A, Mathiesen EB, Johnsen SH, Brox J, Wilsgaard T, Njolstad I, Hansen JB. Serum osteoprotegerin, srankl and carotid plaque formation and growth in a general population - the Tromsø study. J Thromb Haemost. 2010; 8: 898–905.MedlineGoogle Scholar17 Ovchinnikova O, Gylfe A, Bailey L, Nordstrom A, Rudling M, Jung C, Bergstrom S, Waldenstrom A, Hansson GK, Nordstrom P. Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of apoe-deficient mice—brief report. Arterioscler Thromb Vasc Biol. 2009; 29: 1478–1480.LinkGoogle Scholar18 Venuraju SM, Yerramasu A, Corder R, Lahiri A. Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. J Am Coll Cardiol. 2010; 55: 2049–2061.CrossrefMedlineGoogle Scholar19 Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J. Association of osteoprotegerin with human abdominal aortic aneurysm progression. Circulation. 2005; 111: 3119–3125.LinkGoogle Scholar20 Secchiero P, Corallini F, Beltrami AP, Ceconi C, Bonasia V, Di Chiara A, Ferrari R, Zauli G. An imbalanced opg/trail ratio is associated to severe acute myocardial infarction. Atherosclerosis. 2010; 210: 274–277.CrossrefMedlineGoogle Scholar21 Morony S, Tintut Y, Zhang Z, Cattley RC, Van G, Dwyer D, Stolina M, Kostenuik PJ, Demer LL. Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(−/−) mice. Circulation. 2008; 117: 411–420.LinkGoogle Scholar22 Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009; 361: 756–765.CrossrefMedlineGoogle Scholar23 Smith MR, Egerdie B, Hernandez Toriz N, Feldman R, Tammela TL, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A, Leder BZ, Goessl C. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009; 361: 745–755.CrossrefMedlineGoogle Scholar24 Van Campenhout A, Golledge J. Osteoprotegerin, vascular calcification and atherosclerosis. Atherosclerosis. 2009; 204: 321–329.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Serra R, Jiritano F, Bracale U, Ielapi N, Licastro N, Provenzano M, Andreucci M, Rizzuto A, Mastroroberto P and Serraino G (2021) Novel biomarkers in cardiovascular surgery, Biomarkers in Medicine, 10.2217/bmm-2020-0480, 15:4, (307-318), Online publication date: 1-Mar-2021. Pourafkari L, Tajlil A and Nader N (2019) Biomarkers in diagnosing and treatment of acute heart failure, Biomarkers in Medicine, 10.2217/bmm-2019-0134, 13:14, (1235-1249), Online publication date: 1-Oct-2019. Cao Y, Cui C, Zhao H, Pan X, Li W, Wang K and Ma A (2019) Plasma Osteoprotegerin Correlates with Stroke Severity and the Occurrence of Microembolic Signals in Patients with Acute Ischemic Stroke, Disease Markers, 10.1155/2019/3090364, 2019, (1-7), Online publication date: 2-May-2019. Czapla J, Matuszczak S, Kulik K, Wiśniewska E, Pilny E, Jarosz-Biej M, Smolarczyk R, Sirek T, Zembala M, Zembala M, Szala S and Cichoń T (2019) The effect of culture media on large-scale expansion and characteristic of adipose tissue-derived mesenchymal stromal cells, Stem Cell Research & Therapy, 10.1186/s13287-019-1331-9, 10:1, Online publication date: 1-Dec-2019. Raaz-Schrauder D, Schrauder M, Stumpf C, Lewczuk P, Kilian T, Dietel B, Garlichs C, Schlundt C, Achenbach S and Klinghammer L (2017) Plasma levels of sRANKL and OPG are associated with atherogenic cytokines in patients with intermediate cardiovascular risk, Heart and Vessels, 10.1007/s00380-017-0998-z, 32:11, (1304-1313), Online publication date: 1-Nov-2017. Zhao H, Cao Y, Chen H, Xu W, Sun X and Pan X (2017) The association between OPG rs3102735 gene polymorphism, microembolic signal and stroke severity in acute ischemic stroke patients, Gene, 10.1016/j.gene.2017.02.029, 613, (25-29), Online publication date: 1-May-2017. Znorko B, Oksztulska-Kolanek E, Michałowska M, Kamiński T and Pawlak K (2017) Does the OPG/RANKL system contribute to the bone-vascular axis in chronic kidney disease? A systematic review, Advances in Medical Sciences, 10.1016/j.advms.2016.08.001, 62:1, (52-64), Online publication date: 1-Mar-2017. Yin R, Ma A, Pan X and Yang S (2017) Biomarkers of cerebral microembolic signals, Clinica Chimica Acta, 10.1016/j.cca.2017.10.028, 475, (164-168), Online publication date: 1-Dec-2017. O’Regan N, Moxon C, Gegenbauer K, O’Sullivan J, Chion A, Smith O, Preston R, Brophy T, Craig A and O’Donnell J (2017) Marked elevation in plasma osteoprotegerin constitutes an early and consistent feature of cerebral malaria, Thrombosis and Haemostasis, 10.1160/TH15-10-0796, 115:04, (773-780), . Toffoli B, Fabris B, Bartelloni G, Bossi F and Bernardi S (2016) Dyslipidemia and Diabetes Increase the OPG/TRAIL Ratio in the Cardiovascular System, Mediators of Inflammation, 10.1155/2016/6529728, 2016, (1-7), . Robberecht H and Hermans N (2016) Biomarkers of Metabolic Syndrome: Biochemical Background and Clinical Significance, Metabolic Syndrome and Related Disorders, 10.1089/met.2015.0113, 14:2, (47-93), Online publication date: 1-Mar-2016. Hoffmann D, Böker K, Schneider S, Eckermann-Felkl E, Schuder A, Komrakova M, Sehmisch S and Gruber J (2016) In Vivo siRNA Delivery Using JC Virus-like Particles Decreases the Expression of RANKL in Rats, Molecular Therapy - Nucleic Acids, 10.1038/mtna.2016.15, 5, (e298), . Mihai S, Codrici E, Popescu I, Enciu A, Rusu E, Zilisteanu D, Albulescu R, Anton G and Tanase C (2016) Proteomic Biomarkers Panel: New Insights in Chronic Kidney Disease, Disease Markers, 10.1155/2016/3185232, 2016, (1-11), . Higgins C, Isbilir S, Basto P, Chen I, Vaduganathan M, Vaduganathan P, Reardon M, Lawrie G, Peterson L and Morrisett J (2015) Distribution of Alkaline Phosphatase, Osteopontin, RANK Ligand and Osteoprotegerin in Calcified Human Carotid Atheroma, The Protein Journal, 10.1007/s10930-015-9620-3, 34:5, (315-328), Online publication date: 1-Oct-2015. Ueland T, Rollag H, Hartmann A, Jardine A, Humar A, Bignamini A, Åsberg A and Aukrust P (2015) Increased Osteoprotegerin Predicts Poor Virological Outcome During Anticytomegalovirus Therapy in Solid Organ Transplant Recipients, Transplantation, 10.1097/TP.0000000000000227, 99:1, (100-105), Online publication date: 1-Jan-2015. Tsarenok S and Gorbunov V (2015) The levels of osteoprotegerin, transforming growth factor-β, and some cytokines in women with coronary heart disease concurrent with severe osteoporosis, Terapevticheskii arkhiv, 10.17116/terarkh201587939-43, 87:9, (39), . Pérez de Ciriza C, Lawrie A and Varo N (2015) Osteoprotegerin in Cardiometabolic Disorders, International Journal of Endocrinology, 10.1155/2015/564934, 2015, (1-15), . Biscetti F, Porreca C, Bertucci F, Straface G, Santoliquido A, Tondi P, Angelini F, Pitocco D, Santoro L, Gasbarrini A, Landolfi R and Flex A (2014) TNFRSF11B gene polymorphisms increased risk of peripheral arterial occlusive disease and critical limb ischemia in patients with type 2 diabetes, Acta Diabetologica, 10.1007/s00592-014-0664-1, 51:6, (1025-1032), Online publication date: 1-Dec-2014. Albu A, Bondor C, Crăciun A and Fodor D (2014) Circulating osteoprotegerin and asymptomatic carotid atherosclerosis in postmenopausal non diabetic women, Advances in Medical Sciences, 10.1016/j.advms.2014.08.002, 59:2, (293-298), Online publication date: 1-Sep-2014. Pérez de Ciriza C, Lawrie A and Varo N (2014) Influence of pre-analytical and analytical factors on osteoprotegerin measurements, Clinical Biochemistry, 10.1016/j.clinbiochem.2014.05.006, 47:13-14, (1279-1285), Online publication date: 1-Sep-2014. Pérez de Ciriza C, Moreno M, Restituto P, Bastarrika G, Simón I, Colina I and Varo N (2014) Circulating osteoprotegerin is increased in the metabolic syndrome and associates with subclinical atherosclerosis and coronary arterial calcification, Clinical Biochemistry, 10.1016/j.clinbiochem.2014.09.004, 47:18, (272-278), Online publication date: 1-Dec-2014. Cao H, Zhou Q, Wu Y, Li Q, Røe O, Chen Y, Wu Z and Wang D (2013) Preoperative Serum Soluble Receptor Activator of Nuclear Factor-κB Ligand and Osteoprotegerin Predict Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Valve Surgery, The Annals of Thoracic Surgery, 10.1016/j.athoracsur.2013.04.042, 96:3, (800-806), Online publication date: 1-Sep-2013. Einvik G, Flyvbjerg A, Hrubos-Strøm H, Randby A, Frystyk J, Bjerre M, Namtvedt S, Kristiansen H, Nordhus I, Somers V, Dammen T and Omland T (2013) Novel cardiovascular risk markers in depression: No association between depressive symptoms and osteoprotegerin or adiponectin in persons at high risk for sleep apnea, Journal of Affective Disorders, 10.1016/j.jad.2012.05.065, 145:3, (400-404), Online publication date: 1-Mar-2013. Ye Z, Ali Z, Klee G, Mosley T and Kullo I (2013) Associations of Candidate Biomarkers of Vascular Disease with the Ankle-Brachial Index and Peripheral Arterial Disease, American Journal of Hypertension, 10.1093/ajh/hps073, 26:4, (495-502), Online publication date: 1-Apr-2013. Ciccone M, Scicchitano P, Gesualdo M, Zito A, Carbonara R, Locorotondo M, Mandurino C, Masi F, Boccalini F and Lepera M (2013) Serum osteoprotegerin and carotid intima–media thickness in acute/chronic coronary artery diseases, Journal of Cardiovascular Medicine, 10.2459/JCM.0b013e3283561433, 14:1, (43-48), Online publication date: 1-Jan-2013. Kim J, Song T, Yang S, Lee O, Nam H, Kim Y, Kim E, Lee H, Nam C and Heo J (2013) Plasma osteoprotegerin levels increase with the severity of cerebral artery atherosclerosis, Clinical Biochemistry, 10.1016/j.clinbiochem.2013.05.048, 46:12, (1036-1040), Online publication date: 1-Aug-2013. Jansson A, Hartford M, Omland T, Karlsson T, Lindmarker P, Herlitz J, Ueland T, Aukrust P and Caidahl K (2012) Multimarker Risk Assessment Including Osteoprotegerin and CXCL16 in Acute Coronary Syndromes, Arteriosclerosis, Thrombosis, and Vascular Biology, 32:12, (3041-3049), Online publication date: 1-Dec-2012. Grace P, Hurley D, Barratt D, Tsykin A, Watkins L, Rolan P and Hutchinson M (2012) Harnessing pain heterogeneity and RNA transcriptome to identify blood-based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model, Journal of Neurochemistry, 10.1111/j.1471-4159.2012.07833.x, 122:5, (976-994), Online publication date: 1-Sep-2012. Tsioufis C, Aggelis A, Dimitriadis K, Thomopoulos C, Kasiakogias A, Tzamou V, Kyvelou S, Mikhailidis D, Papademetriou V and Stefanadis C (2011) Relationships of osteoprotegerin with albuminuria and asymmetric dimethylarginine in essential hypertension: integrating vascular dysfunction, Expert Opinion on Therapeutic Targets, 10.1517/14728222.2011.642868, 15:12, (1347-1353), Online publication date: 1-Dec-2011. Czapla J, Matuszczak S, Wiśniewska E, Jarosz-Biej M, Smolarczyk R, Cichoń T, Głowala-Kosińska M, Śliwka J, Garbacz M, Szczypior M, Jaźwiec T, Langrzyk A, Zembala M, Szala S and Singh S (2016) Human Cardiac Mesenchymal Stromal Cells with CD105+CD34- Phenotype Enhance the Function of Post-Infarction Heart in Mice, PLOS ONE, 10.1371/journal.pone.0158745, 11:7, (e0158745) Dolzhenko A, Richter T and Sagalovsky S (2016) VASCULAR CALCIFICATION, ATHEROSCLEROSIS AND BONE LOSS (OSTEOPOROSIS): NEW PATHOPHYSIOLOGICAL MECHANISMS AND FUTURE PERSPECTIVES FOR PHARMACOLOGICAL THERAPY, Almanac of Clinical Medicine, 10.18786/2072-0505-2016-44-4-513-534, 44:4, (513-534) Jura-Półtorak A, Szeremeta A, Olczyk K, Zoń-Giebel A and Komosińska-Vassev K (2021) Bone Metabolism and RANKL/OPG Ratio in Rheumatoid Arthritis Women Treated with TNF-α Inhibitors, Journal of Clinical Medicine, 10.3390/jcm10132905, 10:13, (2905) Knyazeva L, Damjanov N, Knyazeva L, Meshcherina N and Goryainov I (2018) EFFECT OF GOLIMUMAB ON IMMUNOLOGICAL MARKERS FOR BONE METABOLISM AND ON ARTERIAL STIFFNESS IN PATIENTS WITH RHEUMATOID ARTHRITIS, Rheumatology Science and Practice, 10.14412/1995-4484-2018-286-292, 56:3, (286-292) Skripnikova I, Abirova E, Alikhanova N and Kosmatova O (2018) Vessel stiffness, calcification and osteoporosis. Common pathogenetic components, Cardiovascular Therapy and Prevention, 10.15829/1728-8800-2018-4-95-102, 17:4, (95-102) September 2010Vol 30, Issue 9 Advertisement Article InformationMetrics https://doi.org/10.1161/ATVBAHA.110.208843PMID: 20720194 Originally publishedSeptember 1, 2010 Keywordsrisk factorsimmune systemcytokinescalciumatherosclerosisPDF download Advertisement