International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


ORAL PRESENTATION

MONDAY 10 NOVEMBER
15:00 – 15:15 HRS

A LOCUS ON CHROMOSOME 7 DETERMINES MARKED UPREGULATION OF OSTEOPONTIN IN MICE WITH DYSTROPHIC CARDIAC CALCIFICATION

Korff S
University of Heidelberg

Co-Authors: 2) Aherrahrou Z, 2) Kaczmarek P M, 2) Axtner S B, 2) Jurat A, 2) Doehring L C, 1) Weichenhan D, 1) Katus H A, 1) Ivandic B T
Institutions: 1) University of Heidelberg,2) University of Luebeck

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 examined a putative inhibitor of calcification, osteopontin, in DCC after transdiaphragmal myocardial freeze-thaw injury. Strong osteopontin expression was found colocalizing 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 the osteopontin locus with C57BL/6NCrlBr, but retained a chromosomal segment from C3H/HeNCrlBr on proximal chromosome 7. Similar to C3H/HeNCrlBr, these mice exhibited strong osteopontin expression and DCC. We concluded 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 and potential candidate encoded by a gene on chromosome 7 is the transforming growth factor-beta1, which was more induced (3.5x) in C3H/HeNCrlBr than in C57BL/6NCrlBr mice.


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