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(Circulation. 2008;117:411-420.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr^(–/–) Mice

Sean Morony, PhD; Yin Tintut, PhD; Zina Zhang, BS; Russell C. Cattley, VMD, PhD; Gwyneth Van, BA; Denise Dwyer, BS; Marina Stolina, PhD; Paul J. Kostenuik, PhD; Linda L. Demer, MD, PhD

From the Departments of Molecular Cellular and Integrative Physiology (S.M.), Medicine (Y.T., Z.Z., L.L.D.), and Physiology (L.L.D.), University of California, Los Angeles, and Departments of Pathology (R.C.C., G.V.) and Metabolic Disorders (S.M., D.D., M.S., P.J.K.), Amgen Inc, Thousand Oaks, Calif.

Correspondence to Linda L. Demer, MD, PhD, Department of Medicine, David Geffen School of Medicine at UCLA, Box 951679, 10833 LeConte Ave, Los Angeles, CA 90095–1679. E-mail ldemer{at}mednet.ucla.edu

Received April 5, 2007; accepted October 22, 2007.

Background— The role of osteoprotegerin in vascular disease is unclear. Recent observational studies show that serum osteoprotegerin levels are associated with the severity and progression of coronary artery disease, atherosclerosis, and vascular calcification in patients. However, genetic and treatment studies in mice suggest that osteoprotegerin may protect against vascular calcification.

Methods and Results— To test whether osteoprotegerin induces or prevents vascular disease, we treated atherogenic diet–fed ldlr^(–/–) mice with recombinant osteoprotegerin (Fc-OPG) or vehicle for 5 months. Vehicle-treated mice developed significant, progressive atherosclerosis with increased plasma osteoprotegerin levels, consistent with observational studies, and 15% of these atherosclerotic lesions developed calcified cartilage-like metaplasia. Treatment with Fc-OPG significantly reduced the calcified lesion area without affecting atherosclerotic lesion size or number, vascular cytokines, or plasma cholesterol levels. Treatment also significantly reduced tissue levels of aortic osteocalcin, a marker of mineralization.

Conclusions— These data support a role for osteoprotegerin in the vasculature as an inhibitor of calcification and a marker, rather than a mediator, of atherosclerosis.

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