Altogether, these notions led us to hypothesize that vascular pericytes could play a critical role in arterial calcification formation and regulation, similar to that of osteoblasts in bone tissue. To confirm this hypothesis, we first assessed the presence of pericytes in our cohort of carotid plaques. We observed CD146 + and NG2 + pericyte cell presence in the lesions but with a significantly more intense staining in the asymptomatic carotid plaques. Of note, no significant difference was noted in terms of CD31 + endothelial staining nor in terms of actin staining, further suggesting that pericytes could be responsible for this difference. Then, we assessed the osteoblastic AA26-9 potential of human primary pericytes in vitro. We showed that human pericytes were able to differentiate into osteoblast-like cells and to mineralize. Finally, we found that pericytes secreted increasing amounts of OPG during osteoblastic differentiation and upon inflammatory stimulation by IL-6 and TNF-a. In other words, pericytes, that have the ability to differentiate into osteoblasts and to secrete high amounts of OPG were found in a significantly higher proportion in the asymptomatic plaques that were precisely characterized by an intense presence of both pericyte cells, OPG, as well as a higher proportion of osteoid metaplasia. As in bone tissue, it is hypothesized that in ectopic calcification, mineral deposition and resorption are two opposite processes tightly balanced and regulated by osteoblast- and osteoclast-like cells. Cells from the monocytic lineage are most likely the precursors of the giant multinucleated cells observed in atherosclerosis lesions. Following on with this hypothesis, we observed that pericytes supernatant inhibited the differentiation of Hu CD14 + cells into osteoclasts, an effect that BOC-D-FMK persisted under IL6 and TNF-a inflammatory stimulation. Given the intense secretion of OPG by pericytes during osteoblastic differentiation and under inflammatory stimulation, we hypothesized that this inhibitory effect was OPG-mediated. Indeed, blockage of OPG using a neutralizing antibody proved efficient in significantly reversing this inhibition.