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 α 2 -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.

Identification of Nestin as a Urinary Biomarker for Acute Kidney Injury

“…It is produced by the liver and secreted into the bloodstream and plays an anti-inflammatory role by inhibiting lipopolysaccharide-induced tumor necrosis factor-α. Furthermore, recent studies suggested that fetuin-A could act as a protective factor to inhibit ectopic calcification in uremic patients and that the decreased serum fetuin-A concentration was associated with a higher mortality in dialysis patients [18,19,20,21,22]. However, the role of fetuin-A in patients with AKI is not well studied.…”

Patients with dental calculus have increased saliva and gingival crevicular fluid fetuin-A levels but no association with fetuin-A polymorphisms

“…Due to a high affinity of fetuin-A to hydroxyapatite, any situation that lowers fetuin-A serum concentration will increase the risk of systemic calcification. 11 It is suggested that fetuin-A inhibits formation and precipitation of the apatite precursor minerals and basic calcium phosphate (BCP). 12 Fetuin-A can inhibit unwanted calcification in circulation without inhibiting bone mineralization.…”

“…14 In transgenic fetuin-A deficient mice, extraskeletal calcification, including soft tissue and peri-vertebral arterial calcification may develop. 11 It was reported that fetuin-A is a good inhibitor candidate of extraosseous calcification, particularly in patients with chronic kidney disease. 15,16 Ketteler et al 17 reported an association between all-cause/cardiovascular mortality and low serum fetuin-A levels in hemodialysis (HD) patients.…”

Up-Regulation of Hepatic Alpha-2-HS-Glycoprotein Transcription by TestosteroneviaAndrogen Receptor Activation

“…Along those lines gene-targeted mice lacking fetuin-A [4] develop severe tissue calcification following mineral and vitamin D-rich diet [5]. Fetuin-A deficiency further contributes to the pathogenesis of cardiovascular calcifications in dialysis patients [6,7,8].…”