Osteoprotegerin is an alpha(v)beta(3)-induced, NF-kappa B-dependent survival factor for endothelial cells

Osteopontin protects endothelial cells from apoptosis induced by growth fac tor withdrawal. This interaction is mediated by the alpha(v)beta(3) integri n and is NF-kappa B-dependent (Scatena, M., Almeida, M., Chaisson, M. L,, F austo, N., Nicosia, R. F., and Giachelli, C. M. (1998) J. Cell Biol. 141, 1 083-1093). In the present study we used differential cloning to identify os teopontin-induced, NF-kappa B-dependent genes in endothelial cells. One of the genes identified in this screen was osteoprotegerin, a member of the tu mor necrosis factor receptor superfamily, By Northern and Western blot anal ysis, 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 fol lowing alpha(v)beta(3) ligation by osteopontin. Osteoprotegerin induction b y osteopontin was time-dependent and observed as early as 3 h following tre atment. 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 endot helial cells with inactive NF-kappa B from apoptosis induced by growth fact or deprivation. These data suggest that alpha(v)beta(3)-mediated endothelia l survival depends on osteoprotegerin induction by NF-kappa B and indicate a new function for osteoprotegerin in endothelial cells.