Regulation of vascular calcification by osteoprotegerin

Vascular calcification contributes to morbidity and mortality in patients with advanced atherosclerosis, diabetes, and renal disease and is associated with reduced elasticity, increased cardiac work, raised blood pressure, and increased cardiovascular events. In atherosclerosis, calcium hydroxyapatite co-localizes with intimal plaque, and in renal disease, these deposits are found predominantly in the medial arterial layer. The prevalence of vascular calcification increases with age with some studies finding greater than 90% affected individuals in a population over 70 years.; The vascular calcification phenotype in opg(-/-) mice was the first evidence of a protective role for osteoprotegerin (OPG), a soluble decoy-receptor for receptor activator of NF-kappaB ligand (RANKL), in the vasculature. However recent observational studies confound this view, suggesting that circulating OPG levels associate with the severity and progression vascular disease and calcification. To test these conflicting views, atherogenic-diet-fed Idlr(-/-) mice were treated with recombinant Fc-OPG; and atherosclerosis and vascular calcification were evaluated. Consistent with observational studies, the progression of atherosclerosis was associated with increased OPG levels. However, concurrent Fc-OPG treatment reduced calcified atherosclerotic lesion area without affecting atherosclerosis or cholesterol levels. These data support a protective role for OPG in the vasculature, as an inhibitor of calcification and a marker, rather that a mediator, of atherosclerosis.; To elucidate the mechanism of this effect of OPG on vascular calcification; vascular tissue, cells, and serum biomarkers were evaluated in OPG-null mice. Consistent with the amorphic nature of the calcified vascular lesions, phosphate levels were elevated in opg(-/-) mice, likely a result of increased bone resorption in these mice. Additionally we found no difference in the aortic expression of bone and cartilage factors, with OPG-deficiency. However, vascular mRNA for ENPP1, which generates inorganic pyrophosphate (PPi), a mineralization inhibitor, was not increased in opg(-/-) mice. Thus, the lack of enpp1 induction, together with remodeling-related hyperphosphatemia, may be important etiological factors in the development of vascular calcification in opg(-/-) mice; and suggest a novel mechanism for the protective role of OPG in the vasculature.