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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2117.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE^–/– Mice

Brian J. Bennett; Marta Scatena; Elizabeth A. Kirk; Marcello Rattazzi; Rebecca M. Varon; Michelle Averill; Stephen M. Schwartz; Cecilia M. Giachelli; Michael E. Rosenfeld

From the Department of Pathobiology and the Interdisciplinary Graduate Program in Nutritional Sciences (B.J.B., E.A.K., R.M.V., M.A., M.E.R.), Department of Bioengineering (M.S., C.M.G.), Department of Pathology (S.M.S., C.M.G., M.E.R.), University of Washington, Seattle, Wash; Dipartimento di Medicina Clinica e Sperimentale (M.R.), Università di Padova, Italy.

Correspondence to Michael E. Rosenfeld, Departments of Pathobiology and Pathology, Box 358050, University of Washington, Seattle, WA 98195. E-mail ssmjm{at}u.washington.edu

Objective— Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE^–/– mice.

Methods and Results— Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG^–/–.apoE^–/– mice) at 20, 40, and 60 weeks of age. Littermate OPG^+/+.apoE^–/– mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG^–/–.apoE^–/– mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG^–/–.apoE^–/– mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells.

Conclusion— OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.

The effect of OPG inactivation in advanced atherosclerotic lesions from apoE^–/– mice was investigated. OPG is a key mediator of bone resorption and has been associated with human and mouse atherosclerosis. OPG inactivation results in larger and more calcified advanced lesions in the innominate arteries of older apoE^–/– mice.

Key Words: apolipoprotein E-deficient mice • atherosclerosis • osteoprotegerin • vascular calcification

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