Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-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-kappaB-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-kappaB-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-kappaB inactivation achieved by over expression of an IkappaB super repressor in endothelial cells completely inhibited osteoprotegerin induction by osteopontin. Finally, purified osteoprotegerin protected endothelial cells with inactive NF-kappaB from apoptosis induced by growth factor deprivation. These data suggest that alpha(v)beta(3)-mediated endothelial survival depends on osteoprotegerin induction by NF-kappaB and indicate a new function for osteoprotegerin in endothelial cells.
Malyankar
U M
UM
Departments of Bioengineering and Immunology, University of Washington, Seattle, Washington 98195, USA.
Scatena
M
M
Suchland
K L
KL
Yun
T J
TJ
Clark
E A
EA
Giachelli
C M
CM
D000818:Animals; D001011:Aorta; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007700:Kinetics; D016328:NF-kappa B / Q000378:metabolism*; D053244:Osteoprotegerin; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D019030:Receptors, Vitronectin / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic
D006023:Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; C506032:Tnfrsf11b protein, rat