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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2058.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Role of Osteoprotegerin in Arterial Calcification

Development of New Animal Model

Yuichi Orita; Hideya Yamamoto; Nobuoki Kohno; Masaaki Sugihara; Hiroaki Honda; Seiichi Kawamata; Shinji Mito; Nwe Nwe Soe; Masao Yoshizumi

From the Department of Molecular and Internal Medicine (Y.O., H.Y., N.K., M.S.), Graduate School of Biomedical Sciences, the Department of Developmental Biology (H.H.), Research Institute for Radiation Biology and Medicine, the Department of Anatomy and Histology (S.K.), Graduate School of Health Sciences, and the Department of Cardiovascular Physiology and Medicine (S.M., N.N.S., M.Y.), Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

Correspondence to Masao Yoshizumi, MD, PhD, Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail yos1956oktbh{at}hiroshima-u.ac.jp

Objectives— Enhanced osteoclastogenesis, increased bone resorption, and osteoporosis have been reported in osteoprotegerin-deficient (OPG (–/–)) mice. OPG (–/–) mice available in Japan usually do not show vascular calcification. We have found that arterial calcification can be quickly induced by a simple procedure in OPG (–/–) mice.

Methods and Results— Male OPG (–/–), OPG (+/–), and OPG (+/+) mice were fed a high phosphate diet from 6 to 10 weeks after birth, and then 1,25-dihydroxyvitamin D3 (calcitriol) was injected for 3 days. We found that severe calcification developed in the media of the aorta in OPG (–/–) mice. Under electron microscopy, calcium deposits were observed in the cytoplasm and extracellular matrix of vascular smooth muscle cells (VSMCs). Neither apoptosis of VSMCs nor infiltration of macrophages was observed. Alkaline phosphatase (ALP) activity of aortic tissue correlated with the calcified lesion area. Mouse aorta and bone extracts revealed an identical pattern by ALP electrophoresis.

Conclusions— Our results demonstrated that OPG had anticalcification activity in the aorta, probably through the downregulation of ALP activity. Because the time course of arterial calcification after the injection of calcitriol is accurate and reproducible, this mouse model will be useful for further investigation of vascular calcification.

Using osteoprotegerin-deficient mice, we established a mouse model in which arterial calcification can be quickly induced by treatment with a high-phosphate diet plus calcitriol injection. This model will allow us to perform detailed pathological and biochemical examinations at desired time points.

Key Words: osteoprotegerin • alkaline phosphate • vascular smooth muscle cells • calcium deposits

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