Osteoprotegerin, vascular calcification and atherosclerosis

Abstract

The association of bone pathologies with atherosclerosis has stimulated the search for common mediators linking the skeletal and the vascular system. Since its initial discovery as a key regulator in bone metabolism, osteoprotegerin (OPG) has become the subject of intense interest for its role in vascular disease and calcification. Studies in vitro and in animal models suggest that OPG inhibits vascular calcification. Paradoxically however, clinical studies suggest that serum OPG levels increase in association with vascular calcification, coronary artery disease, stroke and future cardiovascular events. This has led to an extensive debate on the potential of OPG as a biomarker of vascular disease. However the exact significance and mechanisms by which this bone-regulatory protein influences cardiovascular pathophysiology is still unclear. The need for a more complete picture is being addressed in increasing valuable research indicating OPG as not only a marker but also a mediator of vascular pathology modulating osteogenic, inflammatory and apoptotic responses. By integrating the results of recent experimental research, animal models and clinical studies, this review summarises the present understanding of the role of OPG in vascular disease and calcification.

Figures

Figure 1

The origin of increased OPG. The production of OPG in VSMC and endothelial cells is enhanced by inflammatory cytokines and may reflect endothelial dysfunction. Additionally, the failing myocardium, plaque rupture and other inflamed tissues could contribute to elevated circulating OPG concentrations. LV, left ventricular; MMP, matrix metalloproteases; OPG, osteoprotegerin; VSMC, vascular smooth muscle cells.

Figure 2. OPG as a mediator in vascular disease progression

ALP, alkaline phosphatase; eNOS, endothelial nitric oxide synthase; MMP, matrix metalloproteases; OPG, osteoprotegerin; TRAIL, TNF-related apoptosis-inducing ligand; RANKL, receptor activator of NF-κB ligand; VSMC, vacular smooth muscle cells.