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 α v β 3 integrin and is NF-κB-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-κB-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 α v β 3 ligation by osteopontin. Osteoprotegerin induction by osteopontin was time-dependent and observed as early as 3 h following treatment. NF-κB inactivation achieved by over expression of an IκB super repressor in endothelial cells completely inhibited osteoprotegerin induction by osteopontin. Finally, purified osteoprotegerin protected endothelial cells with inactive NF-κB from apoptosis induced by growth factor deprivation. These data suggest that α v β 3 -mediated endothelial survival depends on osteoprotegerin induction by NF-κB and indicate a new function for osteoprotegerin in endothelial cells.