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Correlation of plasma osteoprotegerin (OPG) and receptor activator of the nuclear factor κB ligand (RANKL) levels with clinical risk factors in patients with advanced carotid atherosclerosis.
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PMID:  23018352     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Osteoprotegerin (OPG) is considered to be a crucial regulatory mediator of bone metabolism by acting as a decoy receptor of the receptor activator of nuclear factor κB ligand (RANKL). OPG and RANKL have further become the subject of intense interest for their potential role in cardiovascular disease. The present study aimed to assess the clinical implication of plasma OPG and RANKL levels in patients with advanced carotid atherosclerosis.
MATERIAL/METHODS: Plasma OPG and RANKL concentrations measured by solid-phase enzyme-linked immunosorbent assay (ELISA) were correlated with medical history, risk factors and medication intake in 131 patients who underwent carotid endarterectomy for vascular repair.
RESULTS: Plasma OPG concentrations were associated with patients' age (p=0.0258), homocysteine levels (p<0.00001), eGFR (p=0.0254), history of diabetes (p=0.0324), statins therapy (p=0.0044), hyperlipidemia (p=0.0407), smoking (p=0.0226) and CAD (p=0.0377). Plasma RANKL concentrations were associated with patients' age (p=0.0191), homocysteine levels (p<0.00001), history of smoking (p=0.0185) and statins therapy (p=0.0004). Diabetes, CAD, smoking status, statins therapy and homocysteine were identified as independent predictors of OPG concentrations (p=0.0157, p=0.0030, p=0.0249, p=0.0047 and p=0.0072, respectively), whereas smoking showed an independent effect for RANKL (p=0.0010).
CONCLUSIONS: The present data reinforce the clinical utility of OPG in carotid atherosclerosis, whereas the clinical implication of RANKL seems uncertain.
Constantinos Giaginis; Aikaterini Papadopouli; Athina Zira; Athanasios Katsargyris; Christos Klonaris; Stamatios Theocharis
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Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Medical science monitor : international medical journal of experimental and clinical research     Volume:  18     ISSN:  1643-3750     ISO Abbreviation:  Med. Sci. Monit.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-28     Completed Date:  2013-02-19     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  9609063     Medline TA:  Med Sci Monit     Country:  Poland    
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Languages:  eng     Pagination:  CR597-604     Citation Subset:  IM    
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens, Greece.
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MeSH Terms
Carotid Artery Diseases / blood,  drug therapy,  pathology*
Middle Aged
Osteoprotegerin / blood*
RANK Ligand / blood*
Risk Factors
Reg. No./Substance:
0/Osteoprotegerin; 0/RANK Ligand; 0/TNFRSF11B protein, human; 0/TNFSF11 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal ID (nlm-ta): Med Sci Monit
Journal ID (iso-abbrev): Med. Sci. Monit
Journal ID (publisher-id): Medical Science Monitor
ISSN: 1234-1010
ISSN: 1643-3750
Publisher: International Scientific Literature, Inc.
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© Med Sci Monit, 2012
Received Day: 24 Month: 8 Year: 2011
Accepted Day: 02 Month: 4 Year: 2012
collection publication date: Year: 2012
Electronic publication date: Day: 01 Month: 10 Year: 2012
Volume: 18 Issue: 10
First Page: CR597 Last Page: CR604
PubMed Id: 23018352
ID: 3560555
Publisher Id: 883485

Correlation of plasma osteoprotegerin (OPG) and receptor activator of the nuclear factor κB ligand (RANKL) levels with clinical risk factors in patients with advanced carotid atherosclerosis
Constantinos Giaginis12ACDE
Aikaterini Papadopouli3BF
Athina Zira1CD
Athanasios Katsargyris3BF
Christos Klonaris3BG
Stamatios Theocharis1ADEG
1Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens, Greece
2Department of Food Science and Nutrition, University of the Aegean, Myrina, Lemnos, Greece
31st Department of Propedeutic Surgery, Medical School, University of Athens, Athens, Greece
Correspondence: Stamatios Theocharis, 1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias str., Goudi, Athens, GR11527, Greece, e-mail:
AStudy Design
BData Collection
CStatistical Analysis
DData Interpretation
EManuscript Preparation
FLiterature Search
GFunds Collection


Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor superfamily, which was originally discovered as an inhibitor of osteoclastogenesis [1]. OPG is a soluble glycoprotein consisting of 380 amino acids, which exists in 2 forms – as a monomeric form of 60 KDa and as homodimeric form linked with disulfide bond of 120 KDa, which is the active form [2]. It is widely expressed in most human tissues, including osteoblasts of the bone, as well as in endothelial and smooth muscle cells of the vascular wall [3]. OPG acts as a soluble decoy substrate to the receptor activator of the nuclear factor κB ligand (RANKL). RANKL, a transmembrane glycoprotein of the TNF superfamily, is expressed by osteoblasts, stromal cells and T lymphocytes and binds to RANK, which is located to the surface of osteoclast precursor cells such as monocytes, macrophages and dendritic cells [4,5]. RANKL-RANK interactions activate nuclear factor κ by degradation of IκB protein by IκB kinase, leading to release of the nuclear factor κB (NFκB), which then translocates to the nucleus in order to initiate the transcription of specific genes required for osteoclast differentiation [6,7]. Binding of OPG to RANKL competitively attenuates RANKL-RANK interactions and inhibits the proliferation and differentiation of osteoclasts and consequently bone resorption [8]. Bone constitutes the largest source of OPG and RANKL molecules. Notably, the OPG/RANKL/RANK axis exerts pleiotropic effects on bone metabolism and hormonal secretion, being considered responsible for ossification and bone mineralization [8]. Moreover, OPG is able to bind TNF-related apoptosis-inducing ligand (TRAIL), which is expressed by T lymphocytes, endothelial and smooth muscle cells and exerts protective effects by preventing apoptotic cell death of infiltrating inflammatory cells during atherosclerosis and cardiovascular disease [9,10].

Atherosclerosis constitutes a chronic inflammatory disease occurring within the artery wall and is a main cause of cardiovascular diseases such as myocardial infarction and stroke [11]. Stress, tobacco smoking, alcohol consumption, hypertension, diabetes mellitus, obesity and dyslipidemia have been identified as important risk factors predisposing to atherosclerosis [12]. Atherosclerotic plaque formation is triggered by endothelial cell activation and dysfunction causing the release of vasoactive molecules, which stimulate an inflammatory response and recruitment/migration of leukocytes into the intima of the arterial wall [13]. The ensuing secretion of cytokines, growth factors and mediators promote vascular smooth muscle cell proliferation and potentiate the inflammatory response associated with arterial remodelling [14,15]. The multi-factorial nature of atherosclerosis involves chronic inflammation at every step from initiation to progression, suggesting that certain clinical risk factors may contribute to the pathogenesis of disease by aggravating the underlying inflammatory process [16].

The strong association between bone pathologies and atherosclerosis has stimulated systematic research for the identification of common molecular mediators linking the skeletal and the vascular systems [17,18]. In this aspect, several bone turnover regulators and structural proteins, including OPG and RANKL, were shown to be expressed within atherosclerotic plaques [19]. Substantial data from animal models have recently suggested that OPG may exert a protective role against pathological calcification within the vascularity, being a potential marker of the onset of atherosclerosis [2025]. Notably, several clinical studies have indicated a strong association between OPG elevation and cardiovascular disease states, including coronary artery disease (CAD), peripheral artery disease (PAD), acute myocardial infarction, heart failure, abdominal aortic aneurism, vascular calcification and stroke [2629]. However, there has been little clinical evaluation of circulating OPG and RANKL in advanced carotid atherosclerosis. Interestingly, it was shown that early and advanced human carotid atherosclerotic lesions presented elevated OPG and RANKL immunoreactivity and mRNA expression [30,31]. Moreover, circulating and tissue OPG elevation was associated with carotid plaque echogenicity and neurological symptomatology [30,32]. Another study based on a healthy population documented an inverse relationship between serum OPG levels and carotid plaque echogenicity [33]. Serum OPG levels were also positively associated with carotid intima thickness in women with gestational diabetes [34]. In view of the above considerations, the present study aimed to assess the plasma OPG and RANKL concentrations in patients with advanced carotid atherosclerosis in relation to medical history, risk factors and medication intake.

Material and Methods

The study enrolled 131 patients that underwent carotid endarterectomy in Laikon Hospital between January 2007 and December 2008. The study was approved by the Hospital Ethics Committee. Informed consent was obtained from all participants. Indication for surgery was a symptomatic carotid stenosis of ≥50% or an asymptomatic carotid stenosis of ≥70% [35]. Patients preoperatively had carotid duplex ultrasound scans, digital subtraction angiograms, or both. Patients or plaques were defined as symptomatic when focal symptoms of cerebral ischemia were present, ipsilateral to the carotid lesions, such as transient ischemic attack, amaurosis fugax, or stroke occurred in the last 6 months. All patients were on antiplatelet treatment preoperatively, which was interrupted 1 week before surgery.

A complete medical history, risk factors and medication intake were recorded, including age, sex, coronary artery disease (CAD) (angina pectoris, myocardial infarction and coronary artery by-pass grafting/percutaneous transluminal coronary angioplasty-CABG/PTCA), diabetes mellitus (controlled with diet, oral hypoglycemic agents or insulin; fasting glucose level ≥126 mg/dL), hyperlipidemia (total cholesterol ≥200 mg/dL), hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or self-report of high blood pressure) [36], peripheral artery disease (PAD), peripheral vascular operation (PVO), smoking status, therapy with statins and angiotensin-converting enzyme (ACE) inhibitors, and serum creatinine concentrations. Estimated glomerular filtration rate (eGFR) was calculated using the simplified modification of diet in renal disease formula (186.3 × serum creatinine−1.154 × age−0.203 (×0.742 if female) (×1.212 if black)) [37]. Plasma homocysteine and c-reactive protein (CRP) were determined by reversed-phase high performance liquid chromatography (HPLC) coupled to a fluorescence detector (ImmuChrom GmbH, Heppenheim, Germany) and BN ProSpec nephelometer (Dade Behring, Siemens Healthcare Diagnostics, Liederbach, Germany), respectively, as previously described [38]. The demographic characteristics of the patients under study are summarized in Table 1.

Determination of plasma OPG and RANKL concentrations by enzyme-linked immunosorbent assay (ELISA)

Plasma OPG and RANKL concentrations were measured by solid-phase ELISA using commercially available kits purchased from R&D Systems Europe, Ltd, UK. The assays of OPG and RANKL are capable of determining total OPG, including monomer, dimer and bound form, and uncomplexed RANKL form, respectively. All procedures were performed according to the manufactures’ protocols and samples were diluted 20-fold. Every sample was run in duplicate, measurements differed by less than 10%, and the mean value was calculated and used for statistical analysis. A standard curve was created, and OPG and RANKL concentrations of the examined samples multiplied by the dilution factor was calculated and expressed in pg/ml. The sensitivity of the OPG assay was 1.4 pg/ml and the intra- and inter-assay precision coefficient of variation ranged between 3.2–4.6% and 5.5–7.7%, respectively, at different levels. The sensitivity of the RANKL assay was 2.1 pg/ml and the intra- and inter-assay precision coefficient of variation ranged between 3.6–4.9% and 6.1–8.2%, respectively, at different levels.

Statistical analysis

The Kolmogorov-Smirnov test was initially applied to assess the normality of distribution of plasma OPG and RANKL concentrations. Plasma OPG concentrations were normally distributed, therefore Student’s t-test analysis was used to evaluate its association with categorical clinical variables. Plasma RANKL concentrations were not normally distributed and therefore the non-parametric method, Mann-Whitney U-test, was applied to assess its association with categorical clinical variables. Results were presented as mean (Standard Deviation-SD) and median (interquartile range-IQR: Q25–Q75) values for plasma OPG and RANKL concentrations, respectively. Spearman rank order correlation analysis was used to evaluate the linear relationship of OPG and RANKL concentration with continuous clinical variables. Multiple regression analysis was performed to assess which clinical variables are independent predictors of OPG and RANKL concentrations. A 2-tailed exact p-value of less than 0.05 was taken to be statistically significant. Statistical analyses were performed using SPSS for Windows (version 11.0; SPSS Inc., Chicago, IL, USA).

Clinical evaluation of plasma OPG concentrations

Plasma OPG concentrations ranged from 40.11 to 361.32 pg/ml with a mean value (SD) of 141.07 pg/ml (±57.02 pg/ml). Kolmogorov-Smirnov testing showed normal distribution for plasma OPG concentrations (K-S d=0.066, p>0.05). Student’s t-test analysis was therefore applied to evaluate the associations between OPG concentrations and patients’ clinical variables (Table 1).

When categorizing by the median age, plasma OPG concentrations were significantly increased in patients over 72 years compared to those under 72 years (Table 1, 150.77±57.49 vs. 128.86±54.47 pg/ml, p=0.0283). Spearman rank order correlation analysis further indicated a positive association between plasma OPG concentrations and patients’ age (Rs=0.1946, p=0.0258). Significant associations of OPG concentrations with homocysteine (Rs=0.3979, p<0.00001) and creatinine (Rs=0.1777, p=0.0455) levels, as well as eGFR (Rs=−0.1983, p=0.0254) were noted. OPG concentrations also showed a trend of correlation with CRP, without reaching statistical significance (Rs=−0.1472, p=0.0998). Diabetic patients presented significantly increased plasma OPG concentrations compared to non-diabetics (Table 1, 157.38±53.39 vs. 134.15±57.37, p=0.0324). Plasma OPG concentrations were significantly increased in patients receiving therapy with statins (161.13±50.71 vs. 131.26±57.61 pg/ml, p=0.0044). Patients with history of hyperlipidemia showed significantly reduced OPG concentrations compared to non-hyperlipidemic patients (134.92±58.22 vs. 157.91±50.60 pg/ml, p=0.0407). Patients with history of smoking presented significantly reduced OPG levels compared to non-smokers (132.32±46.99 vs. 155.69±68.77 pg/ml, p-0.0226). Patients with history of CAD also showed significantly reduced OPG levels (130.17±47.37 vs. 150.85±63.22 pg/ml, p=0.0377). OPG concentrations were not associated with patients’ sex, carotid position, stenosis grade, history of symptoms, hypertension, CABG/PTCA, PAD and PVO and therapy with ACEs (Table 1, p>0.05). OPG concentrations were significantly increased in patients with amaurosis fugax compared to asymptomatic patients (168.41±66.32 vs. 128.79±45.28 pg/ml, p=0.0284).

Multiple regression analysis showed that history of diabetes (B=0.1940, CI=0.0372–0.3507, p=0.0157), CAD (B=0.2487, CI=0.0858–0.4116, p=0.0030), smoking status (B=0.1786, CI=0.0229–0.3343, p=0.0249), therapy with statins (B=0.2480, CI=0.0775–0.4185, p=0.0047) and homocysteine levels (B=0.2155, CI=0.0594–0.3715, p=0.0072) were independent predictor factors of plasma OPG concentrations. In contrast, patients’ age, history of hyperlipidemia and eGFR (or creatinine concentrations if used instead of eGFR) were not found to exert a significant independent effect on OPG concentrations (p>0.05).

Clinical evaluation of plasma RANKL concentrations

Plasma RANKL concentrations ranged from 13.10 to 651.77 pg/ml, with a median value (IQR) of 117.43 pg/ml (37.53–75.77 pg/ml). Kolmogorov-Smirnov test showed that plasma RANKL concentrations were not normally distributed (K-S d=0.337, p<0.01). The non-parametric method, Mann-Whitney U-test, was therefore used to assess the associations between plasma RANKL concentrations and patients’ clinicopathological variables (Table 1).

When categorizing by the median age, plasma RANKL concentrations were significantly increased in patients over 72 years compared to those under 72 years [Table 1, 130.71 (81.14–405.81) vs. 89.73 (28.01–133.77) pg/ml, p=0.0114]. Spearman rank order correlation analysis also revealed a positive association between plasma RANKL concentrations and patients’ age (Rs=0.2045, p=0.0191). Plasma RANKL concentrations were significantly associated with plasma homocysteine (Rs=0.3546, p<0.00001). Plasma RANKL concentrations showed a trend of correlation with eGFR (Rs=−0.1710, p=0.0545), whereas non-associations with serum creatinine (Rs=0.1263, p=0.1365) and CRP (Rs=−0.0811, p=0.3665) concentrations were noted. Patients with history of smoking showed significantly reduced RANKL levels compared to non-smokers [107.73(29.07–287.42) vs. 130.71 (72.50–978.96) pg/ml, p=0.0185]. RANKL concentrations were significantly increased in patients receiving therapy with statins compared to untreated patients (130.71(72.50–578.96) vs. 107.73(29.07–287.42) pg/ml, p=0.0004). Patients with history of PAD also showed increased RANKL levels compared to those with no evidence of PAD, without reaching statistical significance [132.20 (88.92–605.63) vs. 118.81 (29.20–316.55) pg/ml, p=0.0577]. RANKL concentrations were not associated with patients’ sex, carotid position, stenosis grade, history of symptoms, diabetes, hypertension, hyperlipidemia, CAD, CABG/PTCA and PVO and therapy with ACEs (Table 1). RANKL concentrations showed a strong positive correlation with OPG concentrations (Rs=0.3356, p<0.00001).

Multiple regression analysis showed that smoking status (B=0.2952, CI=0.1215–0.4689, p=0.0010) was an independent predictor of plasma RANKL concentrations. In contrast, patients’ age, therapy with statins and homocysteine concentrations were not found to exert a significant independent effect on RANKL concentrations (p>0.05).


In the last few years, a gradually increasing number of animal and human studies have been performed in order to assess the potential role of the OPG/RANKL/RANK axis in vascularity. The most comprehensive data from existing clinical studies reported an association between elevated OPG and/or RANKL levels and the presence, severity and progression of cardiovascular diseases, including carotid atherosclerosis [3034].

In the present study, plasma OPG levels were increased in elderly and diabetic patients with advanced carotid atherosclerotic lesions, who underwent carotid endarterectomy for vascular repair. These findings are consistent with previous clinical studies conducted on different study populations [2629]. RANKL levels were associated with patients’ age, presenting only a trend of correlation with history of diabetes. OPG and RANKL concentrations also showed a positive association with homocysteine levels, a well-established risk factor for cardiovascular disease [39]. On the other hand, we did not find any statistical difference in plasma OPG levels between symptomatic and asymptomatic patients with carotid artery stenosis, which is in contrast with the findings of previous studies [30,32]. However, OPG concentrations were significantly increased in patients with amaurosis fugax compared to asymptomatic patients. In this aspect, recent epidemiological studies have indicated age- and sex-specific actions of OPG in carotid atherosclerosis progression, providing a possible explanation for the above controversy [40,41]. We also showed that increased OPG and RANKL levels were associated with history of PAD, but without reaching statistical significance. In this aspect, Golledge et al recently reported an association between elevated serum OPG levels and impaired endothelium, measured as decreased flow-mediated dilatation of the brachial artery in patients with peripheral artery disease [42]. Patients with clinical stage III or IV PAD also presented increased plasma OPG concentrations in comparison to those without ischemic ulcerations [43,44].

The present study further documented that OPG, but not RANKL levels, were reduced in patients with history of CAD and hyperlipidemia, but with the latter not exerting an independent effect in multiple regression analysis. Both OPG and RANKL levels were also significantly reduced in patients with history of smoking compared to non-smokers. In this aspect, the most comprehensive data to date highlighted the ability of circulating OPG levels to predict the prevalence and severity of CAD [4548]. Plasma OPG levels were increased in patients with acute coronary syndrome compared to those with stable angina or normal coronary arteries, being associated with CAD progression [4548]. However, the inverse correlation between OPG levels and history of CAD found in the present study is not directly opposed to previous data, since the influence of CAD in OPG levels may be complicated by the multiple risk factors governing advanced carotid atherosclerosis of the current study population. Such controversies have also been reported in several clinical studies conducted on general populations for both OPG and RANKL [4951]. Moreover, OPG effects may differ depending on the stage of atherosclerotic lesion. In early stages OPG may be increased in order to protect vessels by activating inflammatory pathways in an effort to compensate vasculature damage [2629]. As atherosclerotic lesion progresses, OPG may become injurious to the vessels or is just unable to reverse the procedure of vascular calcification [2629].

We also found that patients receiving therapy with statins exhibited significantly increased OPG and RANKL levels compared to untreated patients. Statins have been shown to exert many favorable effects, including normalizing atherogenic lipid profile, reduction of inflammation, improvement of endothelial function and decrease of cardiovascular morbidity and mortality [52]. Notably, several recent studies have investigated the effects of statins therapy on circulating OPG and RANKL levels. However, the existing studies have been performed on different cohorts, including patients with diabetes type 2 only or CAD only, as well as patients with both diabetes type 2 and microalbuminuria or hypercholesterolemia [5356]. Among them, 3 studies documented serum OPG elevation during statins therapy (lovastatin or simvastatin therapy) [53,54,56], whereas another study reported OPG reduction during pravastatin therapy [55]. Serum RANKL levels were only assessed in 1 of the above studies, being reduced during lovastatin therapy [55]. It should be noted that the majority of the current study population received therapy with a different statin, atorvastatin (27 out of 43 patients receiving therapy with statins), whereas a smaller proportion of patients received simvastatin, fluvastatin or rosuvastatin therapy (5, 6 and 7 patients, respectively). In this aspect, the existing discrepancies may be ascribed to differences in type of statin, administrated dosage and study population, reinforcing the need for further research in order to determine the molecular basis of statins’ effects on OPG and RANKL levels.

Plasma OPG concentrations were also associated with serum creatinine levels and eGFR, which may be ascribed to the fact that patients with advanced carotid atherosclerosis usually exhibit renal impairment. A trend of correlation between RANKL and eGFR was also noted, but without reaching statistical significance. However, it should also be noted that neither OPG nor RANKL levels were associated with history of hypertension, which may induce renal injury, especially in patients with multiple risk factors. In this context, OPG levels were shown to be increased in predialysis and dialysis patients with chronic kidney disease, being associated with the presence and severity of aortic and coronary calcification [5759]. Notably, taking into consideration that serum OPG levels were reduced within 14 days of renal transplantation, it was supported that OPG elevation in chronic kidney disease patients could be ascribed to its accumulation due to impaired renal clearance [60].

In general, it should be taken into account that the cohorts of the existing clinical studies exhibited considerable variations, as some investigations were restricted to patients with diabetes or CAD, while others were conducted on healthy populations, rendering the information concerning the participants considerably different and not directly comparable [2629]. Furthermore, OPG and RANKL measurements were performed with many different kits, and assays were constructed with the use of different antibodies and calibrators. Many studies were based on serum OPG measurements, while others measured plasma OPG. As OPG was shown to behave differentially in those 2 matrices, the existing results cannot be directly compared [61]. Pre-analytical issues affecting the OPG concentrations in biological samples, such as enzymatic degradation, freeze-thaw and binding to other proteins, still need thorough investigation to assure correct and comparable measurements [26]. These population and analytical issues provide further possible explanations for the controversies amongst the existing clinical data and the present report. Furthermore, the limited clinical value of RANKL found in previous clinical studies and the present report may be ascribed to the fact that the existing assays exclusively measure the levels of uncomplexed RANKL, but not of RANKL that is bound to its decoy receptor OPG. On the other hand, the assays of OPG can determine total OPG, including monomer, dimer and bound form.


In conclusion, the associations of plasma OPG concentrations with medical history, risk factors and medication intake supported evidence for the potential clinical implication of OPG in carotid atherosclerosis, whereas the clinical utility of RANKL seems uncertain. However, it remains unclear whether OPG and/or RANKL play a primary or a secondary causal role in mediating or protecting against vascular injury or are only markers of atherosclerosis progression. Further studies are recommended in order to elucidate the clinical significance of OPG and RANKL levels in cardiovascular pathologies, including carotid atherosclerosis, and to determine if functions related with OPG or its ligand may be targets for future therapeutic interventions.


fn8-medscimonit-18-10-cr597Source of support: Departmental sources

fn9-medscimonit-18-10-cr597Conflict of interest statement

All authors verify that they have not accepted any funding or support from an organization that may in any way gain or lose financially from the results of the present study. All authors verify that they have not been employed by an organization that may in any way gain or lose financially from the results of the present study. None of the authors have any other conflicting interest.

1. Simonet WS,Lacey DL,Dunstan CR,et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone densityCellYear: 199789309199108485
2. Yamaguchi K,Kinosaki M,Goto M,et al. Characterization of structural domains of human Osteoclastogenesis inhibitory factorJ Biol ChemYear: 19982735117239478964
3. Collin-Osdoby P,Rothe L,Anderson F,et al. Receptor activator of NF-κB and osteoprotegerin expression by human microvascular endothelia cell, regulation by inflammatory cytokines, and role in human osteoclastogenesisJ Biol ChemYear: 2001276206597211274143
4. Lacey DL,Timms E,Tan HL,et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activationCellYear: 199893165769568710
5. Hofbauer L,Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseaseJAMAYear: 20042924909515280347
6. Kong YY,Yoshida H,Sarosi I,et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesisNatureYear: 1999397315239950424
7. Gilmore TD. Introduction to NFκB: players, pathways and perspectivesOncogeneYear: 20062566808417072321
8. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANK-L and osteoprotegerinCirc ResYear: 20049510465715564564
9. Emery JG,McDonnell P,Burk MB,et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAILJ Biol ChemYear: 199827314363679603945
10. Sato K,Niessner A,Kopecky SL,et al. TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaqueJ Exp MedYear: 20062032395016418392
11. Hansson GK. Inflammatory mechanisms in atherosclerosisJ Thromb HaemostYear: 2006132831
12. Bonora E. The metabolic syndrome and cardiovascular diseaseAnn MedYear: 200638648016448990
13. Niessner A,Goronzy JJ,Weyand CM. Immune-mediated mechanisms in atherosclerosis: prevention and treatment of clinical manifestationsCurr Pharm DesYear: 20071337011018220809
14. Libby P,Ridker PM,Maseri A. Inflammation and atherosclerosisCirculationYear: 200210511354311877368
15. Spagnoli LG,Bonnano E,Sangiorgi G,Mauriello A. Role of inflammation in atherosclerosisJ Nucl MedYear: 20074818001517942804
16. Mallika V,Goswami B,Rajappa M. Atherosclerosis pathophysiology and the role of novel risk factors: a clinicobiochemical perspectiveAngiologyYear: 2007585132218024933
17. Kiel DP,Kauppila LI,Cupples LA,et al. Bone loss and the progression of abdominal aortic calcification over a 25 year period: The Framingham Heart StudyCalcif Tissue IntYear: 2001682717611683533
18. Schulz E,Arfai K,Liu X,et al. Aortic calcification and the risk of osteoporosis and fracturesJ Clin Endocrinol MetabYear: 20048942465315356016
19. Dhore CR,Cleutjens JP,Lutgens E,et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaquesArterioscler Thromb Vasc BiolYear: 2001211998200311742876
20. Bucay N,Sarosi I,Dunstan CR,et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcificationGenes DevYear: 1998121260689573043
21. Min H,Morony S,Sarosi I,et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclast and prevents vascular calcification by blocking a process ressembling osteoclastogenesisJ Exp MedYear: 20001924637410952716
22. Price PA,June HH,Buckley JR,Williamson MK. Osteoprotegerin inhibits vascular calcification by warfarin and by vitamin DArterioscler Thromb Vasc BiolYear: 20012116101611597934
23. Bennett BJ,Scatena M,Kirk EA,et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in ApoE−/− miceArterioscler Thromb Vasc BiolYear: 20062621172416840715
24. Orita Y,Yamamoto H,Kohno N,et al. Role of osteoprotegerin in arterial calcification: development of new animal modelArterioscler Thromb Vasc BiolYear: 20072720586417615383
25. Morony S,Tintut Y,Zhang Z,et al. Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in Idlr(−/−) miceCirculationYear: 20081174112018172035
26. Nybo M,Rasmussen LM. The capability of plasma osteoprotegerin as a predictor of cardiovascular disease: a systematic reviewEur J EndocrinolYear: 2008159603818697793
27. Papadopouli AE,Klonaris CN,Theocharis SE. Role of OPG/RANKL/RANK axis on the vasculatureHistol HistopatholYear: 20082349750618228207
28. Van Campenhout A,Golledge J. Osteoprotegerin, vascular calcification and atherosclerosisAtherosclerosisYear: 20092043212919007931
29. Venuraju SM,Yerramasu A,Corder R,Lahiri A. Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidityJ Am Coll CardiolYear: 20105520496120447527
30. Golledge J,McCann M,Mangan S,et al. Osteoprotegerin and Osteopontin are expressed at high concentrations within carotid atherosclerosisStrokeYear: 20043516364115143295
31. Schoppet M,Al-Fakhir 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 atherosclerosisJ Clin Endocrinol MetabYear: 20048941041215292354
32. Kadoglou NP,Gerasimidis T,Golemati S,et al. The relationship between serum levels of vascular calcification inhibitors and carotid plaque vulnerabiityJ Vasc SurgYear: 200847556218178454
33. Vik A,Mathiesen E,Noto A,et al. Serum osteoprotegerin is inversely associated with carotid plaque echogenicity in humansAtherosclerosisYear: 20071911283416620835
34. Akinci B,Bemir T,Celtik A,et al. Serum osteoprotegerin is associated with carotid intima media thickness in women with previous gestational dianetesDiab Res Clin PractYear: 20088217278
35. Liapis CD,Bell PR,Mikhailidis D,et al. ESVS guidelines. Invasive treatment for carotid stenosis: indication, techniquesEur J Vasc Endovasc SurgYear: 20093711919286127
36. Howard G,Prineas R,Moy C,et al. Racial and geographic differences in awareness, treatment, and control of hypertension: the reasons for geographic and racial differences in stroke studyStrokeYear: 20063711717816556884
37. Smilde TD,van Veldhuisen DJ,Navis G,et al. Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunctionCirculationYear: 200611415728017015793
38. Giaginis C,Zira A,Katsargyris A,et al. Clinical implication of plasma neutrophil gelatinase-associated lipocalin (NGAL) concentrations in patients with advanced carotid atherosclerosisClin Chem Lab MedYear: 20104810354120406131
39. Castro R,Rivera I,Blom HJ,et al. Homocysteine metabolism, hyperhomocysteinaemia and vascular diseaseJ Inherit Metab DisYear: 20062932016601863
40. Vik A,Mathiesen EB,Johnsen SH,et al. Serum osteoprotegerin, sRANKL and carotid plaque formation and growth in a general population – the Tromsø studyJ Thromb HaemostYear: 2010889890520128863
41. Vik A,Mathiesen EB,Brox J,et al. Relation between serum osteoprotegerin and carotid intima media thickness in a general population – the Tromsø StudyJ Thromb HaemostYear: 2010821333920738762
42. Golledge J,Leicht AS,Growther RG,et al. Determinants of endothelial function in a cohort of patients with peripheral artery diseaseCardiolYear: 20081115156
43. Moran C,McCann M,Karan M,Norman P. Association of osteoprotegerin with human abdominal aortic aneurysm progressionCirculationYear: 200511131192515939823
44. Ziegler S,Kudlacek S,Luger A,Minar E. Osteoprotegerin plasma concentrations correlate with severity of peripheral artery diseaseAtherosclerosisYear: 20051821758016115489
45. Jono S,Otsuki S,Higashikuni Y,et al. Serum osteoprotegerin levels and long-term prognosis in subjects with stable coronary artery diseaseJ Thromb HaemostYear: 2010811707520230427
46. Schoppet M,Sattler AM,Schaefer JR,et al. Increased osteoprotegerin serum levels in men with coronary artery diseaseJ Clin Endocrinol MetabYear: 20038810242812629080
47. Ren MY,Sui SJ,Zhang Y,et al. Increased plasma osteoprotegerin levels are associated with the presence and severity of acute coronary syndromeActa CardiolYear: 2008636152219014006
48. Semb AG,Ueland T,Aukrust P,et al. Osteoprotegerin and soluble receptor activator of nuclear factor-kappa B ligand and risk for coronary events: a nested case-control approach in the prospective EPIC-Norfolk population study 1993–2003Arterioscler Thromb Vasc BiolYear: 2009299758019325145
49. Abedin M,Omland T,Ueland T,et al. Relation of osteoprotegerin to coronary calium and aortic plaque (from the Dallas Heart Study)Am J CardiolYear: 200799188689
50. Kiechl S,Schett G,Schwaiger J,et al. Soluble receptor activator of nuclear factor-kappa B ligand and risk for cardiovascular diseaseCirculationYear: 20071163859117620507
51. Lieb W,Gona P,Larson MG,et al. Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident CVD and mortalityArterioscler Thromb Vasc BiolYear: 20103018495420448212
52. Sadowitz B,Maier KG,Gathan V. Basic science review: Statin therapy-part I: the pleiotropic effects of statins in cardiovascular diseaseVasc Endovascul SurgYear: 20104424151
53. Celinska-Lowenhoff M,Lowenhoff T,Undas A,Gluszko P. Effects of hypolipemic drugs on the osteoprotegerin-RANKL system in patients with coronary artery diseaseThromb HaemostYear: 2007978687017479201
54. Nellemann B,Gormsen LC,Dollerup J,et al. Simvastatin reduces plasma osteoprotegerin in type 2 diabetic patients with microalbuminuriaDiabetes CareYear: 20073031222417804683
55. Mori K,Jono S,Emoto M,et al. Effects of pravastatin on serum osteoprotegerin levels in patients with hypercholesterolemia and type 2 diabetesAngiologyYear: 201061869119147525
56. Nezami N,Safa J,Eftekhar-Sadat AT,et al. Lovastatin raises serum osteoprotegerin level in people with type 2 diabetic nephropathyClin BiochemYear: 20104312949920727867
57. Nitta K,Akiba T,Uchida K,et al. Serum osteoprotegerin levels and the extent of vascular calcification in hemodialysis patientsNephrol Dial TransplantYear: 20041918868915128884
58. Gonnelli S,Montagnani A,Caffarelli C,et al. Osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANK-L) serum levels in patients with chronic hemodialysisJ Endocrinol InvestYear: 2005285343916117195
59. Morena M,Dupuy AM,Jaussent I,et al. A cutt-off value of plasma osteoprotegerin value may predict the presence of coronary artery calcification in chronic kidney disease patientsNephr Dial TransplantYear: 200924338997
60. Sato T,Tominaga Y,Iwasaki Y,et al. Osteoprotegerin levels before and after renal transplantationAm J Kidney DisYear: 200128S1757711576949
61. Chan BY,Buckley KA,Durham BH,et al. Effect of anticoagulants and store temperature on the stability of receptor activator for nuclear factor-kappa B ligand and osteoprotegerin in plasma and serumClin ChemYear: 20034920838514633883

Article Categories:
  • Clinical Research

Keywords: OPG, RANKL, atherosclerosis, carotid, medical history, risk factors.

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