A locus on chromosome 7 determines dramatic up-regulation of osteopontin in dystrophic cardiac calcification in mice.
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 the 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-beta1, which was more induced (3.5x) in C3H/HeNCrlBr than in C57BL/6NCrlBr mice.
Aherrahrou
Zouhair
Z
Department of Medicine II, University of Luebeck, Luebeck, Germany.
Axtner
Susanne B
SB
Kaczmarek
Piotr M
PM
Jurat
Alexandra
A
Korff
Susanne
S
Doehring
Lars C
LC
Weichenhan
Dieter
D
Katus
Hugo A
HA
Ivandic
Boris T
BT
D000818:Animals; D001483:Base Sequence; D002114:Calcinosis / Q000235:genetics*; D009202:Cardiomyopathies / Q000235:genetics*; D015870:Gene Expression; D051379:Mice; D020297:Mice, Congenic; D008969:Molecular Sequence Data; D053495:Osteopontin; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012795:Sialoglycoproteins / Q000097:blood / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin