Extracellular fibrinogen: the bad and the ugly in DMD

Having been for a long time in the radar of Pura Muñoz Cánoves from the CEXS-UPF, she could now demonstrate that the severity in muscular dystrophy is fibrinogen dependent. This fibrin precursor, which is never located outside of the vascular compartment in healthy muscle, is deposited in the extracellular matrix in mdx mice, the animal model for Duchenne muscular dystrophy (DMD). In their paper published in Human Molecular Genetics the researchers could furthermore show that the mechanisms supporting disease progression depend on the αMß2-binding motif of fibrinogen. Once this motif was experimentally eliminated from the fibrinogen gamma chain, this was sufficient to alleviate disease severity in mdx dystrophic muscle.

DMD is still a fatal degenerative muscle disorder. With the discovery of fibrinogen being a critical factor for inflammation-mediated DMD progression, new strategies for treatment could be developed. The counterproductive inflammatory environment established through the αMß2-mediated leukocyte activation could be stopped by selectively targeting this motif leaving its pro-coagulant properties unaltered. The authors also suggest looking into neurodegenerative diseases like Alzheimer’s and multiple sclerosis, because evidence was recently found that interference with the fibrinogen/macrophage axis improves neurodegeneration and stops demyelination in mouse models.

Reference:

Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janué A, Flick MJ, Degen JL, Serrano AL, Muñoz-Cánoves P
Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMß2 leukocyte integrin receptor.
Hum Mol Genet. 2012 Mar 1;

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