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

Alpha2HS-glycoprotein/fetuin-A (Ahsg) is a serum protein preventing soft tissue calcification. In trauma and inflammation, Ahsg is down-regulated and therefore considered a negative acute phase protein. Enhancement of Ahsg expression as a protective serum protein is desirable in several diseases including tissue remodelling after trauma and infection, kidney and heart failure, and cancer. Using reporter gene assays in hepatoma cells combined with electrophoretic mobility shift assays we determined that dexamethasone up-regulates hepatic Ahsg. A steroid response unit at position −146/−119 within the mouse Ahsg promoter mediates the glucocorticoid-induced increase of Ahsg mRNA. It binds the hepatocyte nuclear factor 3β and CCAAT enhancer binding protein β (C/EBP-β). The up-regulation is mediated indirectly via glucocorticoid hormone-induced transcriptional up-regulation in C/EBP-β protein. A high degree of sequence identity in mouse, rat and human Ahsg promoters suggests that the promoter is similarly up-regulated by dexamethasone in all three species. Therefore, our findings suggest that glucocorticoids may be used to enhance the level of Ahsg protein circulating in serum.

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Positive Correlation between Circulating Fetuin A and Severity of Coronary Artery Disease in Military Males

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200601164253 ◽

2020 ◽

Vol 20 ◽

Cited By ~ 1

Author(s):

Reza Afrisham ◽

Maliheh Paknejad ◽

Davod Ilbeigi ◽

Sahar Sadegh-Nejadi ◽

Sattar Gorgani-Firuzjaee ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Military Personnel ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Ectopic Calcification ◽

Dual Function ◽

Fetuin A ◽

Nonalcoholic Fatty Liver ◽

Artery Disease

Introduction: Fetuin-A serves a dual function; its high levels are associated with metabolic syndrome, type 2 diabetes, obesity, insulin resistance, and nonalcoholic fatty liver disease and on the other hand, it serves as a potent inhibitor of vascular ectopic calcification. Because of the opposing findings, the aim of the current study was to investigate serum fetuin-A levels in military personnel males with coronary artery disease (CAD). Methods: In the case-control study, anthropometric and biochemical parameters were determined in 83 military personnel males (43 CAD patients and 40 control subjects). At last, the serum fetuin-A levels were measured using the fetuin-A human enzyme-linked immunosorbent assay (ELISA) kit. Results: A significant differences were detected among the two groups for triglyceride and cholesterol levels (P=0.003 and P=0.002, respectively). The mean fetuin A levels were determined 230.57 ± 63.76 and 286.35 ± 64.07 µg/ml for the control group and the CAD patients, respectively (P<0.001). Fetuin A were significantly correlated to the severity of CAD (r 0.393, P<0.001) and associated with the risk of CAD in subjects (OR [CI] = 1. 144 [1.060–1. 235]; p = 0.001). A cut-off value of 237.4 µg/ml had good sensitivity (76.7%) and specificity (65.0%) for differentiating between two groups [area under curve (AUC) = 0.732 (CI=0.621–0.842); p < 0.001]. Conclusion: Our results indicated that fetuin A levels were positively correlated to the severity of CAD. The findings suggest that there are a possible link between pathogenic mechanisms of atherosclerosis and fetuin A; however, more investigations are needed in this regard.

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Ectopic calcification in fetuin-A deficient mice starts in the microvasculature

Bone ◽

10.1016/j.bone.2011.03.580 ◽

2011 ◽

Vol 48 ◽

pp. S241 ◽

Cited By ~ 3

Author(s):

M. Herrmann⁎ ◽

C. Schaefer ◽

A. Kinkeldey ◽

W. Jahnen-Dechent

Keyword(s):

Ectopic Calcification ◽

Fetuin A ◽

Deficient Mice

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Live Imaging of Calciprotein Particle Clearance and Receptor Mediated Uptake: Role of Calciprotein Monomers

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.633925 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sina Koeppert ◽

Ahmed Ghallab ◽

Sarah Peglow ◽

Camilla Franziska Winkler ◽

Steffen Graeber ◽

...

Keyword(s):

Endothelial Cells ◽

Calcium Phosphate ◽

Soft Tissues ◽

Anion Exchange Chromatography ◽

Exchange Chromatography ◽

Ectopic Calcification ◽

Inflammasome Activation ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Fetuin A

BackgroundThe liver-derived plasma protein fetuin A is a systemic inhibitor of ectopic calcification. Fetuin-A stabilizes calcium phosphate mineral initially as ion clusters to form calciprotein monomers (CPM), and then as larger multimeric consolidations containing amorphous calcium phosphate (primary CPP, CPP 1) or more crystalline phases (secondary CPP, CPP 2). CPM and CPP mediate excess mineral stabilization, transport and clearance from circulation.MethodsWe injected i.v. synthetic fluorescent CPM and studied their clearance by live two-photon microscopy. We analyzed organ sections by fluorescence microscopy to assess CPM distribution. We studied cellular clearance and cytotoxicity by flow cytometry and live/dead staining, respectively, in cultured macrophages, liver sinusoidal endothelial cells (LSEC), and human proximal tubule epithelial HK-2 cells. Inflammasome activation was scored in macrophages. Fetuin A monomer and CPM charge were analyzed by ion exchange chromatography.ResultsLive mice cleared CPP in the liver as published previously. In contrast, CPM were filtered by kidney glomeruli into the Bowman space and the proximal tubules, suggesting tubular excretion of CPM-bound calcium phosphate and reabsorption of fetuin A. Fetuin-A monomer clearance was negligible in liver and low in kidney. Anion exchange chromatography revealed that fetuin A monomer was negatively charged, whereas CPM appeared neutral, suggesting electrochemical selectivity of CPM versus fetuin A. CPM were non-toxic in any of the investigated cell types, whereas CPP 1 were cytotoxic. Unlike CPP, CPM also did not activate the inflammasome.ConclusionsFetuin-A prevents calcium phosphate precipitation by forming CPM, which transform into CPP. Unlike CPP, CPM do not trigger inflammation. CPM are readily cleared in the kidneys, suggesting CPM as a physiological transporter of excess calcium and phosphate. Upon prolonged circulation, e.g., in chronic kidney disease, CPM will coalesce and form CPP, which cannot be cleared by the kidney, but will be endocytosed by liver sinusoidal endothelial cells and macrophages. Large amounts of CPP trigger inflammation. Chronic CPM and CPP clearance deficiency thus cause calcification by CPP deposition in blood vessels and soft tissues, as well as inflammation.

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Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

10.1101/577239 ◽

2019 ◽

Cited By ~ 3

Author(s):

Anne Babler ◽

Carlo Schmitz ◽

Andrea Büscher ◽

Marietta Herrmann ◽

Felix Gremse ◽

...

Keyword(s):

Soft Tissue ◽

Molecular Genetic ◽

Extracellular Fluid ◽

Molecular Genetic Analysis ◽

Ectopic Calcification ◽

Special Importance ◽

Soft Tissue Calcification ◽

Fetuin A ◽

Tissue Calcification ◽

Deficient Mice

AbstractObjectiveCalcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic target that could be influenced by dietary of parenteral supplementation.Approach and ResultsWe studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the TRPM6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with dietary phosphate restriction, magnesium supplementation, or by parenteral administration of fetuin-A or pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement.ConclusionsWe show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, pyrophosphate, and magnesium. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, pyrophosphate and magnesium levels.Subject CodesAnimal Models of Human Disease, Fibrosis, Inflammation, Proteomics, Peripheral Vascular Disease

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