Elsevier

Clinical Biochemistry

Volume 47, Issue 18, December 2014, Pages 272-278
Clinical Biochemistry

Circulating osteoprotegerin is increased in the metabolic syndrome and associates with subclinical atherosclerosis and coronary arterial calcification

https://doi.org/10.1016/j.clinbiochem.2014.09.004Get rights and content

Highlights

  • OPG is increased in the metabolic syndrome and associates with increasing cardiovascular factors.

  • Patients with higher intima media thickness have increased OPG concentration.

  • Patients with atheroma plaques or coronary artery calcification have higher OPG levels.

  • OPG is expressed in adipose tissue.

  • OPG expression is higher in adipose tissue from patients with the metabolic syndrome.

Abstract

Context

The relationship between osteoprotegerin (OPG) a glycoprotein related to bone metabolism and the metabolic syndrome (MS) has not been established.

Objective

The aim of this study is to evaluate OPG concentration in patients with MS and its association with subclinical atherosclerosis and coronary arterial calcification (CAC).

Materials/methods

The study included 238 asymptomatic patients. MS was diagnosed according to the NCEP/ATPIII guidelines. OPG was measured by ELISA. All subjects underwent ultrasonography of the common carotid arteries to measure intima-media thickness (IMT) and evaluate the presence of atheroma plaques. In a subgroup (n = 39) CAC was quantified by ECG-triggered cardiac computed tomography. Adipose tissue was excised from 25 patients and OPG expression by RT-PCR and immunohistochemistry was studied.

Results

Patients with the MS (n = 60) had higher OPG than patients without (n = 178) (p < 0.05). OPG correlated with IMT (r = 0.2, p = 0.005) and patients with atheroma plaques had higher OPG (p = 0.008) and also those with coronary artery calcification (p < 0.05).

OPG expression was confirmed in adipose tissue (n = 12) and the expression was significantly higher in patients with MS than in those without (p = 0.003).

Conclusions

This study shows that OPG may potentially be a biomarker for cardiovascular risk/damage in the MS and identifies adipose tissue as a potential source of OPG.

Introduction

Osteoprotegerin (OPG) is a soluble glycoprotein member of the tumor necrosis factor (TNF) receptor superfamily, originally discovered as an inhibitor of osteoclastogenesis. Biochemically, OPG is a basic secretory glycoprotein composed of 380 aminoacids and seven structural domains which exists as a more active monomeric form (∼ 60-kDa) and a homodimeric form [1].

OPG is part of the OPG/receptor activator of NF-кB ligand (RANKL)/receptor activator of NF-кB (RANK) pathway. The RANKL/OPG/RANK axis has been shown to regulate bone remodeling. RANKL–RANK interaction leads to the transcription of specific genes required for osteoclast differentiation. OPG acts as a soluble decoy substrate to the receptor activator of RANKL and competes with RANK, inhibiting RANKL–RANK interactions and thus proliferation and differentiation of osteoclasts and consequently bone resorption [2].

In addition to being central to regulating RANK–RANKL interactions in bone metabolism, several studies suggest that there is a potential role of OPG in mediating cardiovascular damage [1], [3]. In vitro studies indicate that OPG is expressed in cells involved in atheroma plaque development and progression, such as arterial smooth muscle cells [4], endothelial cells [5] and megakaryocytes [6]. Moreover, OPG expression is enhanced in explanted human carotid atherosclerotic plaques [7].

Human studies show a positive relationship between circulating OPG, vascular damage and cardiovascular disease. Indeed, elevated serum OPG levels have been found associated with atherosclerosis [8] and carotid intima media thickness (IMT) in a general population [9] and with increased risk of cardiovascular disease and mortality [10], [11].

There is scarce information of OPG circulating levels in the MS, a cluster of cardiovascular risk factors.

The aims of the present work were 1) to evaluate OPG circulating levels in patients with the MS and its association with the presence of subclinical atherosclerosis and coronary arterial calcification and 2) to explore whether adipose tissue is a source of OPG.

Section snippets

Study population

This case control study was performed in 238 apparently healthy subjects (51% males, 60 ± 1 years; 49% women, 59 ± 1 years) attending the Cardiovascular Risk Area of the Clinic Universidad de Navarra for a general check-up. The demographic and clinical characteristics of the study population are summarized in Table 1.

All participants underwent a complete medical examination and anthropometric measurements were taken. Subjects were free from clinically apparent atherosclerotic disease based on the

Demographic and clinical characteristics of study population

After complete clinical examination, subjects were divided in two groups: those with (n = 60) and those without (n = 178) MS. The demographic and clinical characteristics of the study population are displayed in Table 1. As expected, patients with MS exhibited significantly (p < 0.001) higher BMI, systolic arterial pressure, diastolic arterial pressure, waist circumference, glucose, and triglyceride levels and lower HDL-cholesterol than those without MS. Besides, total cholesterol was significantly

Discussion

The main findings of the current study are: 1) circulating OPG is increased in patients with the MS and associates with increasing number of cardiovascular factors, 2) carotid IMT is higher in patients with high serum OPG levels, 3) patients with carotid atheroma plaques or coronary artery calcification have higher OPG levels than those without and 4) OPG is expressed in adipose tissue samples and its expression is increased in MS patients.

Author contributions

Carmen Pérez de Ciriza, María Moreno and Patricia Restituto made substantial contributions to data acquisition, analysis and interpretations of data as well as drafting the article and revising it.

Gorka Bastarrika and Isabel Simón performed the intima-media thickness and coronary artery calcium measurements and revised the manuscript.

Inmaculada Colina recruited the patients and revised the manuscript.

Nerea Varo made substantial contributions to conception and design, revised the article and

Disclosure statement

The authors have nothing to disclose.

Acknowledgments

Financial support for part of this study was provided by a grant from J.L. Castaño Foundation from the Sociedad Española de Química Clínica (SEQC).

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