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Phosphate-Induced Vascular Calcification: Role of Pyrophosphate and Osteopontin

Koba A. Lomashvili^*, Scott Cobbs^*, Randolph A. Hennigar, Kenneth I. Hardcastle and W. Charles O’Neill^*

*Renal Division, Department of Medicine, Department of Pathology, and Department of Chemistry, Emory University, Atlanta, Georgia

Correspondence to W. Charles O’Neill, Emory University, Renal Division, WMB 338, 1639 Pierce Drive, Atlanta, Georgia. Phone: 404-727-3922; Fax: 404-727-3425; E-mail: woneill{at}emory.edu

ABSTRACT. Hyperphosphatemia is thought to underlie medial vascular calcification in advanced renal failure, but calcification can occur in other conditions in the absence of hyperphosphatemia, indicating that additional factors are important. To identify these factors, a model of medial calcification in rat aorta in vitro was developed. Aortic rings from rats were incubated in serum-free medium for 9 d, and calcification was measured as incorporation of ⁴⁵Ca and confirmed by histology and x-ray diffraction. No calcification occurred in normal vessels despite elevated free Ca²⁺ and PO₄^3– concentrations of 1.8 mM and 3.8 mM, respectively, but mechanical injury resulted in extensive calcification in the media. Co-incubation studies revealed that normal aortas produced a soluble inhibitor of calcification in injured vessels that was destroyed by alkaline phosphatase. Culture of normal aortas with alkaline phosphatase resulted in calcification of the elastic lamina identified as hydroxyapatite by x-ray diffraction. This effect of alkaline phosphatase was not due to dephosphorylation of osteopontin (OPN), and calcification was not increased in aortas from OPN-deficient mice. The inhibitor was identified as pyrophosphate on the basis of the calcification induced in aortas cultured with inorganic pyrophosphatase, the inhibition of calcification in injured aortas by pyrophosphate, and the production of inhibitory levels of pyrophosphate by normal aortas. No calcification occurred under any conditions at a normal PO₄^3– concentration. It is concluded that elevated concentrations of Ca²⁺ and PO₄^3– are not sufficient for medial vascular calcification because of inhibition by pyrophosphate. Alkaline phosphatase can promote calcification by hydrolyzing pyrophosphate, but OPN is not an endogenous inhibitor of calcification in rat aorta.

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