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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1420.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Calcification of Advanced Atherosclerotic Lesions in the Innominate Arteries of ApoE-Deficient Mice

Potential Role of Chondrocyte-Like Cells

Marcello Rattazzi; Brian J. Bennett; Florian Bea; Elizabeth A. Kirk; Jerry L. Ricks; Mei Speer; Stephen M. Schwartz; Cecilia M. Giachelli; Michael E. Rosenfeld

From the Department of Pathobiology (M.R., F.B., E.A.K., J.L.R., M.E.R.), the Interdisciplinary Graduate Program in Nutritional Sciences (B.J.B., E.A.K., M.E.R.), the Department of Bioengineering (M.S., C.M.G.), and the Department of Pathology (S.M.S., C.M.G., M.E.R.), University of Washington, Seattle.

Correspondence to Michael E. Rosenfeld, Department of Pathobiology, Box 353410, University of Washington, Seattle, WA 98195. E-mail ssmjm{at}u.washington.edu

Objective— Advanced atherosclerotic lesions in the innominate arteries of chow-fed apolipoprotein E–deficient mice become highly calcified with 100% frequency by 75 weeks of age. The time course, cell types, and mechanism(s) associated with calcification were investigated.

Methods and Results— The deposition of hydroxyapatite is preceded by the formation of fibro-fatty nodules that are populated by cells that morphologically resemble chondrocytes. These cells are spatially associated with small deposits of hydroxyapatite in animals between 45 and 60 weeks of age. Immunocytochemical analyses with antibodies recognizing known chondrocyte proteins show that these cells express the same proteins as chondrocytes within developing bone. Histological and electron microscopic analyses of lesions from animals between 45 and 60 weeks of age show that the chondrocyte-like cells are surrounded by dense connective tissue that stains positive for type II collagen. Nanocrystals of hydroxyapatite can be seen within matrix vesicles derived from the chondrocyte-like cells. In mice between 75 and 104 weeks of age, the lesions have significantly reduced cellularity and contain large calcium deposits. The few remaining chondrocyte-like cells are located adjacent to or within the large areas of calcification.

Conclusions— Calcification of advanced lesions in chow-fed apolipoprotein E–deficient mice occurs reproducibly in mice between 45 and 75 weeks of age. The deposition of hydroxyapatite is mediated by chondrocytes, which suggests that the mechanism of calcification may in part recapitulate the process of endochondral bone formation.

Advanced atherosclerotic lesions in the innominate arteries of chow-fed apolipoprotein E–deficient mice become highly calcified. The cell types associated with calcification were investigated. The cells mediating the calcification have a chondrocyte-like phenotype. The process of calcification within advanced lesions of apoE–/– mice may recapitulate endochondral bone formation.

Key Words: atherosclerosis • calcification • chondrocytes • apolipoprotein E–deficient mice

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