Circulating osteoprotegerin is increased in the metabolic syndrome and associates with subclinical atherosclerosis and coronary arterial calcification
Graphical abstract
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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2022, Bone ReportsCitation Excerpt :Because of the small number of studies included it is not possible to make any conclusion about a possible association between Klotho and arterial calcification. In total, 38 studies are published that investigated a possible association between OPG and arterial calcification (Barbarash et al., 2016; Chai et al., 2017; Davaine et al., 2016; Diederichsen et al., 2017; Golovkin et al., 2016; Liu et al., 2019; Torii et al., 2016; Bernandes et al., 2019; Abedin et al., 2007; Asanuma et al., 2007; Bakhireva et al., 2008; Berezin and Kremzer, 2013a; Bezerra et al., 2005; Dekker et al., 2021; Esteghamati et al., 2014; Frost et al., 2008; Golledge et al., 2008; Hosbond et al., 2014a; Ketlogetswe et al., 2015; Kiani et al., 2017; Lieb et al., 2010; Liu et al., 2020; Mohammadpour et al., 2012; Nugroho and Widorini, 2017; Omland et al., 2007; Park et al., 2006; Pérez de Ciriza et al., 2014; Poornima et al., 2014; Poornima et al., 2018; Quercioli et al., 2012; Vinholt et al., 2013; Hosbond et al., 2014b; Hwang et al., 2012; Kwon et al., 2016; Pesaro et al., 2018; Salari et al., 2017; Stȩpień et al., 2012; Wilund et al., 2008). Nineteen studies indicated a positive association (Barbarash et al., 2016; Chai et al., 2017; Liu et al., 2019; Torii et al., 2016; Abedin et al., 2007; Asanuma et al., 2007; Dekker et al., 2021; Esteghamati et al., 2014; Golledge et al., 2008; Ketlogetswe et al., 2015; Liu et al., 2020; Nugroho and Widorini, 2017; Omland et al., 2007; Park et al., 2006; Pérez de Ciriza et al., 2014; Poornima et al., 2014; Kwon et al., 2016; Stȩpień et al., 2012) two a negative association (Golovkin et al., 2016; Mohammadpour et al., 2012) and seventeen no association (Davaine et al., 2016; Diederichsen et al., 2017; Bernandes et al., 2019; Bakhireva et al., 2008; Bezerra et al., 2005; Frost et al., 2008; Hosbond et al., 2014a; Kiani et al., 2017; Lieb et al., 2010; Poornima et al., 2018; Quercioli et al., 2012; Vinholt et al., 2013; Hosbond et al., 2014b; Hwang et al., 2012; Pesaro et al., 2018; Salari et al., 2017; Wilund et al., 2008).
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2021, Nutrition and Functional Foods in Boosting Digestion, Metabolism and Immune HealthEffect of osteoprotegerin gene polymorphisms on the risk of cervical spondylotic myelopathy in a Chinese population
2018, Clinical Neurology and NeurosurgeryCitation Excerpt :OPG is highly expressed in the liver, kidney, bone marrow as well as other tissues and produced by various cell types like endothelial cells and smooth muscle cells [10]. Additionally, OPG regulates bone metabolism through essential roles in the formation, activation and survival of osteoclasts and play an important role in atherosclerosis, arterial calcification and vascular disease [11]. OPG suppresses bone resorption through binding to its ligand, receptor activator nuclear factor-kappaB ligand, and thus, prevents the binding to its receptor [12].
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2018, Clinica Chimica ActaThe role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases
2018, Pharmacology and TherapeuticsCitation Excerpt :The mechanisms underlying the regulation of OPG levels, OPG polymorphism and metabolic diseases are currently not fully elucidated. Statistical analysis showed no significant difference in the distribution of the OPG A163G polymorphism in diabetic patients and control groups (Guo, Hu, Zhang, Wang, & Liu, 2013; Perez de Ciriza et al., 2014; Soysal-Atile et al., 2015). RANKL is mainly expressed on infiltrating T cells and activated ECs.