Despite the debate on the role of circulating OPG in atherosclerotic disease [31], as an experimental study reported that exogenous OPG treatment lead to endothelial and vascular smooth cell dysfunction by promoting the production of reactive oxygen species, which may underlie vascular injurious effects in conditions such as hypertension [32], the phenotype of OPG-knockout mice ultimately indicates circulating OPG as a biomarker, rather than a mediator, of atherosclerosis, as OPG-deficient mice develop early onset arterial calcification [33]. This evidence concerns the gene TNFRSF11B and Hypertension.