Bone Morphogenetic Protein-7 Inhibits Vascular Calcification Induced by High Vitamin D in Mice

Bone Morphogenetic Protein-7 Inhibits Vascular Calcification Induced by High Vitamin D in Mice

YANG HO KANG,^1,2,3 JUNG SOOK JIN,² DONG WON YI^1,3 and SEOK MAN SON^1,2,3

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
²Medical Research Institute, Pusan National University Hospital, Busan, Korea
³Diabetes Center and Endocrine Clinic, Pusan National University Yangsan Hospital, Yangsan, Korea

Vascular calcification refers to the deposition of calcium phosphate in cardiovascular tissues, including arteries and myocardium. Vascular calcification is frequently associated with cardiovascular disease. Recently, bone morphgenetic protein-7 (BMP-7) has been proposed to play an inhibitory role in vascular calcification, but its inhibitory effect has not been fully elucidated. We therefore tested the hypothesis that BMP-7 inhibits vascular calcification by using two conditions, high levels of vitamin D and phosphate, each of which could enhance vascular calcification. C57BL/6 mice were treated for 3 days with high vitamin D (500,000 IU/kg/day) in the presence or absence of recombinant human BMP-7 (rhBMP-7). Expression levels of osteopontin and osteocalcin, markers of the osteoblastic phenotype, were assessed by immunohistochemical staining or Western blotting analysis. Vitamin D increased calcium staining in thoracic aortas and hearts and the expression levels of osteopontin and osteocalcin in mice. Importantly, pretreatment for 7 days and subsequent treatment for 3 days with rhBMP-7 (10 μg/kg/day) abolished the vitamin D-mediated increases in the above parameters. In addition, human aortic smooth muscle cells (HASMCs) were cultured with high β-glycerophosphate, a phosphate donor, for 2 weeks in the presence or absence of rhBMP-7. High β-glycerophosphate increased expression levels of osteopontin and osteocalcin as well as calcium staining in HASMCs, but these changes were attenuated by treatment with BMP-7. Thus, BMP-7 inhibits vascular calcification associated with high levels of vitamin D or phosphate. We propose that BMP-7 treatment may be helpful in reducing the risks of cardiovascular disease related to vascular calcification.

keywords —— BMP-7; vascular calcification; vitamin D; phosphate; vascular smooth muscle cell

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Tohoku J. Exp. Med., 2010, 221, 299-307

Correspondence: Seok Man Son, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, 626-770, Korea.

e-mail: sonsm@pusan.ac.kr