The serum protein α2–Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification
Cora Schäfer, … , Thorsten Schinke, Willi Jahnen-Dechent
Cora Schäfer, … , Thorsten Schinke, Willi Jahnen-Dechent
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):357-366. https://doi.org/10.1172/JCI17202.
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Article Cardiology

The serum protein α2–Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification

Abstract

Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein α2–Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as an important inhibitor of ectopic calcification acting on the systemic level. Ahsg-deficient mice are phenotypically normal, but develop severe calcification of various organs on a mineral and vitamin D–rich diet and on a normal diet when the deficiency is combined with a DBA/2 genetic background. This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation. The same underlying principle may contribute to many calcifying disorders including calciphylaxis, a syndrome of severe systemic calcification in patients with chronic renal failure. Taken together, our data demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide a novel therapeutic concept to prevent ectopic calcification accompanying various diseases.

Authors

Cora Schäfer, Alexander Heiss, Anke Schwarz, Ralf Westenfeld, Markus Ketteler, Jürgen Floege, Werner Müller-Esterl, Thorsten Schinke, Willi Jahnen-Dechent

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Serum chemistry of Ahsg-deficient mice. (a) Serum electrolytes are given...
Serum chemistry of Ahsg-deficient mice. (a) Serum electrolytes are given as the mean ± SE of at least six mice for each measurement (**P < 0.01). Where there are no error bars, the SEs were too small to be visible. (b) Sera from C57BL/6-Ahsg+/+ (filled circles) and DBA/2-Ahsg+/+ mice (filled squares) both inhibited the de novo formation of BCP from supersaturated solutions of calcium and phosphate with an IC50 of 0.8% serum. Serum from C57BL/6-Ahsg–/– (open circles) and DBA/2-Ahsg–/– (open squares) mice inhibited at a much reduced rate (IC50 5.2% and 6.8% serum, respectively). (c) Reconstitution of BCP precipitation inhibition. Note that the reduced inhibition of BCP precipitation by sera from Ahsg-deficient mice could be restored to the WT level by adding back purified mouse serum Ahsg. (d) Serum electrolyte concentrations in normal and calciphylaxis patients (*P < 0.05). (e) Inhibition of BCP precipitation by sera from three healthy subjects (filled circles) and eight calciphylaxis patients (open circles). Note that the inhibition of BCP precipitation is greatly reduced in all calciphylaxis patients. (f) Serum reconstitution by purified human Ahsg in serum of a calciphylaxis patient. Note that the reduced inhibition of BCP precipitation by serum from the calciphylaxis patient could be restored to normal levels by adding back purified human serum Ahsg.