AIMS: Desmin, the muscle-specific intermediate filament protein, is a major 
target in dilated cardiomyopathy and heart failure in humans and mice. The 
hallmarks of desmin-deficient (des(-/-)) mice pathology include pronounced 
myocardial degeneration, extended fibrosis, and osteopontin (OPN) 
overexpression. We sought to identify the molecular and cellular events 
regulating adverse cardiac remodelling in des(-/-) mice and their potential link 
to OPN.
METHODS AND RESULTS: In situ hybridization, histology, and immunostaining 
demonstrated that inflammatory cells and not cardiomyocytes were the source of 
OPN. RNA profile comparison revealed that activation of inflammatory pathways, 
sustained by innate immunity mechanisms, predominated among all changes 
occurring in degenerating des(-/-) myocardium. The expression of the most highly 
up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× 
and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. 
To evaluate the role of OPN, we generated des(-/-)OPN(-/-) mice and compared 
their cardiac function and remodelling indices with those of des(-/-). 
Osteopontin promoted cardiac dysfunction in this model since des(-/-)OPN(-/-) 
mice showed 53% improvement of left ventricular function, paralleled to an up to 
44% reduction in fibrosis. The diminished fibrotic response in the absence of 
OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 
levels, associated with an impaired galectin-3 secretion by OPN-deficient 
infiltrating macrophages.
CONCLUSION: Cardiomyocyte death due to desmin deficiency leads to inflammation 
and subsequent overexpression of a series of remodelling modulators. Among them, 
OPN seems to be a major regulator of des(-/-) adverse myocardial remodelling and 
it functions at least by potentiating galectin-3 up-regulation and secretion.