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J. Biol. Chem., Vol. 283, Issue 21, 14815-14825, May 23, 2008

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Hierarchical Role of Fetuin-A and Acidic Serum Proteins in the Formation and Stabilization of Calcium Phosphate Particles^*

Alexander Heiss¹, Thomas Eckert^¶, Anke Aretz^||, Walter Richtering^¶, Wim van Dorp^**, Cora Schäfer, and Willi Jahnen-Dechent

From the Helmholtz Institute for Biomedical Engineering, Biointerface Group, ^¶Institute for Physical Chemistry, and ^||Central Facility for Electron Microscopy, RWTH Aachen University, 52074 Aachen, Germany, the Institute for Solid State Research, Research Center Juelich, 52425 Juelich Germany, and ^**Kennemer Gasthuis, 2000 AK Haarlem, The Netherlands

The serum protein fetuin-A is a potent systemic inhibitor of soft tissue calcification. Fetuin-A is highly effective in the formation and stabilization of protein-mineral colloids, referred to as calciprotein particles (CPPs). These particles ripen in vitro in a two-step process, indicated by a morphological conversion from spheres to larger prolate ellipsoids. Using a combined light scattering and electron microscopic imaging approach we determined that the second-stage particles resulted from a highly anisotropic outgrowth of the first-stage particles. Electron microscopy of ascites fluid from a patient with calcifying peritonitis revealed particles reminiscent of secondary CPPs. Thus, CPPs form in the body and undergo the two-step ripening at least in pathological conditions. Unlike in vitro generated CPPs, ascites-derived CPPs contained little fetuin-A but large amounts of albumin. This prompted us to study the role of fetuin-A combined with other serum proteins in CPP formation. Fetuin-A was indispensable for primary CPP formation. Albumin and acidic proteins in general greatly enhanced the fetuin-A triggered formation of secondary CPPs and, thus, substituted substantial amounts of fetuin-A without loss of inhibition of calcium phosphate precipitation. Thus, direct mineral deposition from solute in the body is unlikely even at low fetuin-A serum levels as long as sufficient bulk acidic protein is available. Collectively fetuin-A and other acidic bulk plasma proteins may be considered as mineral chaperones mediating the stabilization, safe transport, and clearance in the body of calcium and phosphate as colloidal complexes, thus, preventing ectopic calcification.

Received for publication, December 5, 2007 , and in revised form, March 20, 2008.

^* This work was funded by the priority program of the Deutsche Forschungsgemeinschaft "Principles of Biomineralization."; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Helmholtz Institute for Biomedical Engineering, Biointerface Group, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. Tel.: 49-241-8088719; Fax: 49-241-8082573; E-mail: alexander.heiss{at}post.rwth-aachen.de.

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