A Locus on Chromosome 7 Determines Dramatic Up-Regulation of Osteopontin in Dystrophic Cardiac Calcification in Mice

Zouhair Aherrahrou, Susanne B. Axtner, Piotr M. Kaczmarek, Alexandra Jurat, Susanne Korff, Lars C. Doehring, Dieter Weichenhan, Hugo A. Katus, Boris T. Ivandic*

*Corresponding author for this work
25 Citations (Scopus)

Abstract

Calcification of necrotic tissue is frequently observed in chronic inflammation and atherosclerosis. A similar response of myocardium to injury, referred to as dystrophic cardiac calcinosis (DCC), occurs in certain inbred strains of mice. We now examined a putative inhibitor of calcification, osteopontin, in DCC after transdiaphragmal myocardial freeze-thaw injury. Strong osteopontin expression was found co-localizing with calcification in DCC-susceptible strain C3H/HeNCrlBr, which exhibited low osteopontin plasma concentrations otherwise. Osteopontin mRNA induction was 20-fold higher than in resistant strain C57BL/6NCrlBr, which exhibited fibrous lesions without calcification and little osteopontin expression. Sequence analysis identified several polymorphisms in calcium-binding and phosphorylation sites in osteopontin cDNA. Their potential relevance for DCC was tested in congenic mice, which shared die osteopontin locus with C57BL/6NCrlBr, but retained a chromosomal segment from C3H/HeNCrlBr on proximal chromosome 7. These mice exhibited strong osteopontin expression and DCC comparable to C3H/HeNCrlBr suggesting that a trans-activator of osteopontin transcription residing on chromosome 7 and not the osteopontin gene on chromosome 5 was responsible for the genetic differences in osteopontin expression. A known osteopontin activator encoded by a gene on chromosome 7 is the transforming growth factor-β1, which was more induced (3.5x) in C3H/HeNCrlBr than in C57BL/6NCrlBr mice.

Original languageEnglish
JournalAmerican Journal of Pathology
Volume164
Issue number4
Pages (from-to)1379-1387
Number of pages9
ISSN0002-9440
DOIs
Publication statusPublished - 01.01.2004

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