Osteoprotegerin is an αvβ3-induced, NF-κB-dependent survival factor for endothelial cells

Osteopontin protects endothelial cells from apoptosis induced by growth factor withdrawal. This interaction is mediated by the alpha(v)beta(3) integrin and is NF-kappa B-dependent (Scatena, M., Almeida, M., Chaisson, M. L,, Fausto, N., Nicosia, R. F., and Giachelli, C. M. (1998) J. Cell Biol. 141, 1083-1093). In the present study we used differential cloning to identify osteopontin-induced, NF-kappa B-dependent genes in endothelial cells. One of the genes identified in this screen was osteoprotegerin, a member of the tumor necrosis factor receptor superfamily, By Northern and Western blot analysis, osteoprotegerin mRNA and protein levels were very low in endothelial cells plated on the non-integrin cell attachment factor, poly-D-lysine. In contrast, osteoprotegerin mRNA and protein levels were induced 5-7-fold following alpha(v)beta(3) ligation by osteopontin. Osteoprotegerin induction by osteopontin was time-dependent and observed as early as 3 h following treatment. NF-kappa B inactivation achieved by over expression of an I kappa B super repressor in endothelial cells completely inhibited osteoprotegerin induction by osteopontin. Finally, purified osteoprotegerin protected endothelial cells with inactive NF-kappa B from apoptosis induced by growth factor deprivation. These data suggest that alpha(v)beta(3)-mediated endothelial survival depends on osteoprotegerin induction by NF-kappa B and indicate a new function for osteoprotegerin in endothelial cells.