RT Journal Article
SR Electronic
T1 Soft tissue calcification in mice is governed by fetuin-A, pyrophosphate and magnesium
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 577239
DO 10.1101/577239
A1 Anne Babler
A1 Carlo Schmitz
A1 Andrea Büscher
A1 Marietta Herrmann
A1 Felix Gremse
A1 Theo Gorgels
A1 Jürgen Floege
A1 Willi Jahnen-Dechent
YR 2019
UL http://biorxiv.org/content/early/2019/03/14/577239.abstract
AB Objective Soft tissue calcifications are mostly benign adaptations to ageing, injury or inflammation. However, calcifications 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 severe soft tissue calcifications with premature ageing and organ failure, while fetuin-A deficient C57BL/6 mice remain healthy.Approach and Results We studied the calcification in progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice. We analyzed by DNA sequencing and gene expression analysis candidate risk genes involved in the strong calcification phenotype of fetuin-A deficient DBA/2 mice. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate expression of 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 calcium measurement of affected tissues.Conclusions We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major systemic inhibitors of calcification, namely fetuin-A, pyrophosphate, and magnesium, identifying these compounds as therapeutic targets in the treatment of calcifications. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, pyrophosphate and magnesium levels.