Journal Article

Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the α<sub>M</sub>β<sub>2</sub> leukocyte integrin receptor

Berta Vidal, Esther Ardite, Mònica Suelves, Vanessa Ruiz-Bonilla, Anna Janué, Matthew J. Flick, Jay L. Degen, Antonio L. Serrano and Pura Muñoz-Cánoves

in Human Molecular Genetics

Volume 21, issue 9, pages 1989-2004
Published in print May 2012 | ISSN: 0964-6906
Published online March 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds012
Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor

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In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin αMβ2-mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fibγ390-396A) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the αMβ2 binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/αMβ2 blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-αMβ2 interactions may provide a novel strategy for DMD treatment.

Journal Article.  8718 words.  Illustrated.

Subjects: Genetics and Genomics

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