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      Novel Insights into Uremic Vascular Calcification: Role of Matrix Gla Protein and Alpha-2-Heremans Schmid Glycoprotein/Fetuin

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          Cardiovascular mortality is markedly increased in the dialysis population when compared to non-uremic subjects. Vascular and valvular calcifications are most frequently found in dialysis patients at risk and are independent predictors of cardiovascular death in this population. Traditionally, the presence of hyperphosphatemia and an increased calcium × phosphate product was considered a major pathomechanistic condition leading to excessive vascular and soft-tissue calcifications in uremic subjects. Recent studies in knockout mice, however, revealed that deficiencies in calcium-regulatory proteins may also directly contribute to the development of extraosseus calcifications. α<sub>2</sub>-Heremans Schmid glycoprotein and matrix Gla protein are important inhibitors of calcification in vivo and there is novel evidence available that a deficiency in such proteins is involved in the pathogenesis of cardiovascular calcifications in dialysis patients.

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          Most cited references 5

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          Cloning and targeted deletion of the mouse fetuin gene.

          We proposed that the alpha2-Heremans Schmid glycoprotein/fetuin family of serum proteins inhibits unwanted mineralization. To test this hypothesis in animals, we cloned the mouse fetuin gene and generated mice lacking fetuin. The gene consists of seven exons and six introns. The cystatin-like domains D1 and D2 of mouse fetuin are encoded by three exons each, whereas a single terminal exon encodes the carboxyl-terminal domain D3. The promoter structure is well conserved between rat and mouse fetuin genes within the regions shown to bind transcription factors in the rat system. Expression studies demonstrated that mice homozygous for the gene deletion lacked fetuin protein and that mice heterozygous for the null mutation produced roughly half the amount of fetuin protein produced by wild-type mice. Fetuin-deficient mice were fertile and showed no gross anatomical abnormalities. However, the serum inhibition of apatite formation was compromised in these mice as well as in heterozygotes. In addition, some homozygous fetuin-deficient female ex-breeders developed ectopic microcalcifications in soft tissues. These results corroborate a role for fetuin in serum calcium homeostasis. The fact that generalized ectopic calcification did not occur in fetuin-deficient mice proves that additional inhibitors of phase separation exist in serum.
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            Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats.

            In the present study we report the discovery of a novel protein-mineral complex in the serum of rats treated with doses of the bone-active bisphosphonate etidronate that inhibit normal bone mineralization. The composition of this high molecular mass protein-mineral complex consists of about 18% mineral, 80% fetuin, and 2% matrix Gla protein (MGP) by weight, and the presence of the complex in serum after an injection of 8 mg etidronate/100 g of body weight elevates calcium by 1.8-fold (to 4.3 mm), phosphate by 1.6-fold (to 5.6 mm), and MGP by 25-fold (to 12 microg/ml). The serum mineral complex reaches maximal levels at 6 h after subcutaneous injection of etidronate and is subsequently cleared from serum by 24 h. This highly specific complex of fetuin, MGP, and mineral prevents the growth, aggregation, and precipitation of the mineral component, which indicates that the previously reported calcification inhibitory activities of fetuin and MGP may be related to their ability to form stable complexes with nascent mineral nuclei. Treatment with the vitamin K-antagonist warfarin prevents the increase in serum MGP after etidronate injection, which shows that the increase in serum MGP is due to new synthesis and that the gamma-carboxylation of MGP is necessary for its binding to the serum mineral complex.
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              The Serum Protein α2-HS Glycoprotein/Fetuin Inhibits Apatite Formationin Vitroand in Mineralizing Calvaria Cells


                Author and article information

                Blood Purif
                Blood Purification
                S. Karger AG
                30 August 2002
                : 20
                : 5
                : 473-476
                aDepartment of Nephrology and Clinical Immunology, and bIZKF BioMAT, University Hospital Aachen; cDivision of Nephrology, University Hospital Würzburg, Germany, and dCARIM, University of Maastricht,TheNetherlands
                63554 Blood Purif 2002;20:473–476
                © 2002 S. Karger AG, Basel

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                Tables: 1, References: 23, Pages: 4
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