Osteoprotegerin is a key regulator of bone metabolism involved in the immune response, hematopoiesis, and endothelial dysfunction. It seems to be implicated in angiogenesis and may represent a link between bone and vascular system. Although its role in bone is well recognized, its involvement in vasculature remains to be established. In inflammatory conditions, OPG is constitutively released by endothelial cells and smooth muscle cells, and therefore is able to participate in blood vessels formation induced by endothelial progenitor cells (EPCs). In this study we attempted to determine, in vitro the precise role of OPG in angiogenesis process induced by a subpopulation of EPCs called “endothelial colony-forming cells” (ECFCs), and on neovessel formation in vivo.We found that OPG causes phenotype changes of ECFCs via the activation of different molecular pathways targeting cell clonogenicity, differentiation, proliferation, migration and adhesion. Our results suggest that OPG may interact with ECFCs through its binding to syndecan-1, to induce an anti-adhesive effect and thereby promoting ECFCs migration through a SDF-1/CXCR4 dependant pathway and the ERK1/2, Akt and the mTOR pathways activation. OPG can intervene on the autocrine effect of ECFCs by inducing their adhesion to activated endothelium and their tubulogenesis, and potentiate their paracrine effects by inducing SDF-1 release. Alternatively, it can promote ECFCs survival, probably, in a αVβ3 integrin-dependent manner. In vivo, OPG potentiates FGF-2 proangiogenic effects and may participate in tumour growth, invasion and metastasis, possibly through inhibition of tumour cell apoptosis but also by promoting tumour angiogenesis.
