The serum protein α2–Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification
Cora Schäfer, Alexander Heiss, Anke Schwarz, Ralf Westenfeld, Markus Ketteler, Jürgen Floege, Werner Müller-Esterl, Thorsten Schinke, Willi Jahnen-Dechent
Cora Schäfer, Alexander Heiss, Anke Schwarz, Ralf Westenfeld, Markus Ketteler, Jürgen Floege, Werner Müller-Esterl, Thorsten Schinke, Willi Jahnen-Dechent
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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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The ectopic calcification in DBA/2-Ahsg–/– mice leads to high blood pres...
The ectopic calcification in DBA/2-Ahsg–/– mice leads to high blood pressure, renal failure, and secondary hyperparathyroidism. (a) Blood pressure was recorded in 4- to 5-month-old Ahsg+/+ and Ahsg–/– mice on a C57BL/6 (B6) and a DBA/2 (D2) genetic background. Values are presented as mean ± SE in mmHg. Note that systolic blood pressure (white bars) and diastolic blood pressure (black bars) are significantly elevated (**P < 0.0001) in DBA/2-Ahsg–/– mice (n = 12) compared with pressures in DBA2/Ahsg+/+ (n = 13), C57BL/6-Ahsg–/– (n = 20), and C57BL/6-Ahsg+/+ mice (n = 20). (b) Macroscopic view of the kidney at 9 months of age shows severe calcification and hydronephrosis in DBA/2-Ahsg–/– mice but not in DBA2/Ahsg+/+ littermates (left). Urinary albumin was measured in Ahsg+/+ and Ahsg–/– mice on a C57BL/6 and a DBA/2 genetic background (right). Severe albuminuria was observed in DBA/2-Ahsg–/– mice. (c) Determination of serum concentrations of intact parathyroid hormone (iPTH) and the bone parameters bone volume per total volume (BV/TV), osteoblast number (ObN), and osteoclast number (OcN) in 9-month-old DBA/2-Ahsg–/– and DBA/2-Ahsg+/+ littermates (*P < 0.05). Note the presence of hyperparathyroidism, osteopenia, and an increased number of osteoclasts in DBA/2-Ahsg–/– mice (n = 6 for all parameters).