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Multifunctional Roles for Serum Protein Fetuin-A in Inhibition of Human Vascular Smooth Muscle Cell Calcification

Joanne L. Reynolds^*, Jeremy N. Skepper, Rosamund McNair^*, Takeshi Kasama, Kunal Gupta^*, Peter L. Weissberg^*, Willi Jahnen-Dechent and Catherine M. Shanahan^*

^* Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom; Multi-Imaging Centre, Department of Anatomy, Cambridge, United Kingdom; Department of Materials Science and Metallurgy, University of Cambridge, Cambridge, United Kingdom, and The Institute of Physical and Chemical Research, Hatoyama, Saitama, Japan; and IZKF Biomat Aachen University Clinics, Aachen, Germany

Address correspondence to: Dr. Catherine M. Shanahan, Division of Cardiovascular Medicine, Level 6, ACCI, Box 110, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. Phone: 44-1223-331504; Fax: 44-1223-331505; cs131{at}mole.bio.cam.ac.uk

Received for publication October 29, 2004. Accepted for publication July 2, 2005.

Vascular calcification predicts an increased risk for cardiovascular events/mortality in atherosclerosis, diabetes, and ESRD. Serum concentrations of ₂-Heremens-Schmid glycoprotein, commonly referred to as fetuin-A, are reduced in ESRD, a condition associated with an elevated circulating calcium x phosphate product. Mice that lack fetuin-A exhibit extensive soft tissue calcification, which is accelerated on a mineral-rich diet, suggesting that fetuin-A acts to inhibit calcification systemically. Western blot and immunohistochemistry demonstrated that serum-derived fetuin-A co-localized with calcified human vascular smooth muscle cells (VSMC) in vitro and in calcified arteries in vivo. Fetuin-A inhibited in vitro VSMC calcification, induced by elevated concentrations of extracellular mineral ions, in a concentration-dependent manner. This was achieved in part through inhibition of apoptosis and caspase cleavage. Confocal microscopy and electron microscopy–immunogold demonstrated that fetuin-A was internalized by VSMC and concentrated in intracellular vesicles. Subsequently, fetuin-A was secreted via vesicle release from apoptotic and viable VSMC. Vesicles have previously been identified as the nidus for mineral nucleation. The presence of fetuin-A in vesicles abrogated their ability to nucleate basic calcium phosphate. In addition, fetuin-A enhanced phagocytosis of vesicles by VSMC. These observations provide evidence that the uptake of the serum protein fetuin-A by VSMC is a key event in the inhibition of vesicle-mediated VSMC calcification. Strategies aimed at maintaining normal circulating levels of fetuin-A may prove beneficial in patients with ESRD.

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