Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident CVD and mortality

Cardiovascular diseases (CVD) develop over the human life-course and acute CVD events are often preceded by progressive modifications in the vessel wall referred to as vascular remodeling.1 Understanding the biologic basis of vascular remodeling is, therefore, critical to prevent disease progression and clinical CVD events. Initially described in the context of bone mass regulation,2 RANK (receptor activator of nuclear factor kappa-B), RANK ligand (RANKL), and osteoprotegerin represent an interesting putative pathway in vascular remodeling and atherosclerotic disease.3 OPG acts as a decoy receptor for RANKL,3 thereby interfering with RANKL-binding to its cell-surface receptor RANK. The RANK-RANKL interaction triggers vascular permeability,4 cytokine release, monocyte transmigration and monocyte matrix metalloproteinase activity.5 In patients with unstable angina (as compared to stable angina), higher expression of RANKL in T-cells and of monocytic RANK have been reported.6 OPG is expressed in the vascular system, including endothelial and smooth muscle cells and is modulated by pro-inflammatory cytokines like interleukin-1 and tumor necrosis factor (TNF) alpha.5 It also serves as a survival factor for endothelial cells.7 In addition, OPG and RANKL were both found in atherosclerotic lesions.5 Mice with targeted disruption of the OPG gene display medial calcification of the aorta and renal arteries8 and OPG application inhibited Vitamin D-induced and warfarin-induced vascular calcification in rats.9 Clinical studies have observed higher circulating OPG levels in patients with unstable angina and with acute myocardial infarction, but not in patients with stable angina or established coronary disease suggesting that the OPG/RANK/RANKL system might modulate plaque stability.3, 6, 10 In addition, OPG was positively associated with the severity of coronary artery disease11 and predicted heart failure hospitalizations and mortality in patients with acute coronary syndromes.12 Few moderate sized epidemiological studies have examined the relations of OPG and RANKL to CVD events and mortality in the community.13–15 In the Bruneck study, for example, positive associations of OPG13 and RANKL14 with incident CVD have been reported. In a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, baseline OPG levels were associated with incident coronary events, but not baseline RANKL levels.16 Given the above mentioned clinical and experimental evidence, we aimed to assess whether circulating OPG and RANKL concentrations were associated with incident CVD events and mortality as well as with key CVD risk factors and coronary calcification, an important intermediate phenotype in the CVD continuum.