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

TLDR

Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein alpha2‑Heremans‑Schmid glycoprotein (Ahsg, fetuin‑A) as a systemic inhibitor of ectopic calcification. In Ahsg‑deficient mice, severe organ calcification occurs on both high‑mineral and normal diets—especially with a DBA/2 background—without altering calcium or phosphate levels, due to reduced extracellular fluid inhibition of mineral formation. Our data show that impaired Ahsg activity contributes to disorders such as calciphylaxis and that restoring Ahsg function offers a therapeutic strategy to prevent ectopic calcification.

Abstract

Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein alpha2-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.