Background - Abdominal aortic aneurysm ( AAA) is characterized by destruction of the arterial media associated with loss of vascular smooth muscle cells, infiltration of mononuclear cells, and high concentration of metalloproteinases ( MMPs) and cytokines. Osteoprotegerin (OPG) has recently been identified in atherosclerosis. The presence and functional importance of OPG in human AAA was investigated. Methods and Results - In 146 men with small AAA followed up by ultrasound for 3 years, serum OPG was weakly correlated with aneurysm growth rate. Western analysis showed 3-, 8-, and 12-fold-greater OPG concentrations in human AAA biopsies compared with biopsies of atherosclerotic narrowed aorta (1.4 +/- 0.1 versus 0.5 +/- 0.1 ng/mg tissue; P = 0.002), postmortem nondiseased abdominal aorta (1.4 +/- 0.1 versus 0.2 +/- 0.1 ng/mg tissue; P < 0.001), and nondiseased thoracic aorta (1.4 +/- 0.1 versus 0.1 +/- 0.06 ng/mg tissue; P < 0.001). Healthy human aortic vascular smooth muscle cells incubated with recombinant human (rh) OPG (0 to 20 ng rhOPG/10(5) cells per 1 mL per 24 hours) developed an aneurysmal phenotype defined by impaired cell proliferation (P < 0.001), increased apoptosis ( P < 0.01), and increased MMP-9 (92 kDa) expression (P < 0.001). Incubation of monocytic THP-1 cells with 1 ng rhOPG/10(5) cells per 1 mL per 24 hours induced a 2-fold increase in MMP-9 expression (P < 0.001), a 1.5-fold increase in MMP-2 activity (P = 0.005), and a 2-fold stimulation of IL-6 production in these cells (P = 0.02). Finally, secretion of OPG from human AAA explant was abrogated by treatment with the angiotensin II blocker irbesartan, with the reduction in secreted levels averaging 63.0 +/- 0.9 ng/mg tissue per 48-hour period. Conclusions - These findings support a role for OPG in the growth of human AAA and suggest a potential benefit for angiotensin II blockade in slowing aneurysm expansion.