ReviewOsteoprotegerin, vascular calcification and atherosclerosis
Introduction
A large number of studies have demonstrated a relationship between bone pathology and vascular disease. The coexistence of osteoporosis and features of atherosclerosis, particularly vascular calcification, has been consistently demonstrated and is most prevalent in postmenopausal women and elderly people [1], [2], [3], [4], [5]. These observations suggest that there are common pathways which negatively affect bone metabolism and the vasculature. New insights in this field are emerging since the discovery of osteoprotegerin (OPG) in 1997 as a key regulator in bone turnover [6], [7], [8].
In a mouse model, deficiency of OPG (OPG−/−) resulted in severe osteoporosis but also the unexpected phenotype of vascular calcification [9]. Since this combination of osteoporotic bone loss and arterial mineral accumulation mirrors similar associations seen in patients, OPG was suggested as a key link between bone and vascular disease [10]. Although most animal studies support a protective role for OPG in the vasculature [11], observational studies in patients have paradoxically shown a positive association between serum OPG levels and clinical cardiovascular disease [12]. Whether elevated OPG is simply a marker of vascular damage, represents a counter-regulatory mechanism aimed to limit vascular disease or actively mediates disease progression is not immediately clear. To understand its complete mode of action on the interplay between bone and vascular disease, the pleiotrophic and reciprocal relations between OPG and calcification, inflammation and apoptosis as well as those of its ligands must be taken into consideration.
Section snippets
The OPG/RANK/RANKL/TRAIL system
OPG is a member of the tumor necrosis factor (TNF)-related family and part of the OPG/receptor activator of NF-кB ligand (RANKL)/receptor activator of NF-кB (RANK) triad. This cytokine network regulates the differentiation and activation of osteoclasts and hence the critical balance between bone formation (osteoblasts) and bone resorption (osteoclasts). RANKL expressed on osteoblastic, stromal and T cells binds to RANK on the surface of osteoclasts, monocytic and dendritic cells [13].
Vascular medial calcification
A study of OPG−/− mice generated on a mixed genetic background provided the first evidence for a role of OPG in the vasculature since surprisingly, 2/3rd of the animals displayed medial calcification of the renal arteries and aorta [9]. According to the passive theory, such calcification could result from arterial accumulation of matrix products liberated from uncontrolled osteoclast degradation of bone. Interestingly however, these arteries are sites of endogenous OPG expression in normal mice
Human studies of OPG in vascular disease
Over recent years, numerous clinical studies have consistently reported higher serum levels of OPG in association with cardiovascular outcome including coronary artery disease (CAD), vascular calcification, advanced atherosclerosis, diabetic complications, heart failure, abdominal aortic aneurysm and cardiovascular mortality [12]. In addition to the reports outlined in an excellent review by Kiechl et al. [12], here we summarise the main results and discuss the recent clinical studies
Mechanism underlying the vascular role of OPG
The data from clinical studies consistently report an association between OPG and the presence, severity and progression of a broad range of cardiovascular diseases. Whether OPG is a marker or rather plays a causal role in mediating or protecting against vascular injury is presently unclear. The mechanisms underlying the postulated role of OPG in atherosclerosis may involve endothelial and ventricular dysfunction, inflammation and calcification. A number of investigators have studied the
Concluding remarks
Clearly, the vascular role of OPG is multifaceted and depends on the interplay with its ligands, RANKL and TRAIL, and a bidirectional modulation involving osteogenic, inflammatory and apoptotic responses.
Animal studies generally favour a protective role of OPG, particularly in terms of vascular calcification. At least a minimal amount of endogenous arterial OPG seems necessary to protect against vascular calcification. In addition to inhibiting apoptotic passive calcification, the ability of
Funding
National Institute of Health, USA (RO1 HL080010-01) National, Health and Medical Research Council, Australia (Project grant 540405).
Research Advanced Program faculty grant from James Cook University (Townsville, Australia).
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Serum OPG/TRAIL ratio predicts the presence of cardiovascular disease in people with type 2 diabetes mellitus
2022, Diabetes Research and Clinical PracticeCitation Excerpt :In animal models, OPG appears to exert a protective role against vascular calcification, but promotes atherosclerosis development and progression through its proinflammatory and profibrotic effects on the vessel wall [9]. Observational studies have shown a positive association between serum OPG and clinical CVD [10], and in people with T2DM, OPG also performs well as a biomarker of coronary artery disease, peripheral vascular disease, poor glycaemic control and progression of albuminuria [11-13]. Some research groups have combined OPG and TRAIL measurements and utilised OPG/TRAIL ratio as a biomarker of increased CV risk.
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