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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Ahsg deficiency in DBA/2 mice leads to severe ectopic calcification on a...
Ahsg deficiency in DBA/2 mice leads to severe ectopic calcification on a normal diet. (a) Radiological analysis of 9-month-old male DBA/2-Ahsg+/+ and DBA/2-Ahsg–/– littermate mice. Note the punctuate soft tissue calcification of the thorax, kidneys, and testes in DBA/2-Ahsg–/– mice. (b) Histological analysis of 7-month-old DBA/2-Ahsg+/+ and DBA/2-Ahsg–/– mice. Plastic-embedded tissues were sectioned and prepared with von Kossa staining and H&E counterstaining. Note the positive staining of calcified lesions in DBA/2-Ahsg–/–, but not in littermate DBA/2-Ahsg+/+ mice. Lesions were extracellular in dilated tubules of kidney cortex tissue. Lesions were often associated with atrophied glomeruli. The myocardium (myocard) contained lesions with a fibrosis capsule. Lung tissue contained numerous spherical, scale-like, calcified deposits blocking alveoli. Subdermal adipose tissue contained large calcified nodules. (c) Electron micrograph of kidney tubule interstitium (top). The electron-dense mineral deposits were first detected in foam cell–like phagocytes infiltrating the extracellular space between tubular cells and the basement membrane. Energy dispersive x-ray analysis of the electron dark mineral deposit in these cells identified Ca and P as the major elements present in this sample (bottom).