Published Online
on January 2, 2008

A more recent version of this article appeared on January 22, 2008

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Submitted on April 5, 2007
Accepted on October 22, 2007

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, and 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.

^* To whom correspondence should be addressed. E-mail: ldemer{at}mednet.ucla.edu.

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.

Key words: atherosclerosis • calcification • osteoprotegerin • RANK ligand

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Clinical Summaries
Circulation 2008 117: 331-332. [Full Text]

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