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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  • dc.contributor.author Vidal Iglesias, Bertaca
  • dc.contributor.author Ardite, Estherca
  • dc.contributor.author Suelves, Mònicaca
  • dc.contributor.author Ruiz Bonilla, Vanesa, 1979-ca
  • dc.contributor.author Janué, Annaca
  • dc.contributor.author Flick, Matthew J.ca
  • dc.contributor.author Degen, Jay L.ca
  • dc.contributor.author Serrano, Antonio L.ca
  • dc.contributor.author Muñoz Cánoves, Pura, 1962-ca
  • dc.date.accessioned 2013-06-13T12:01:53Z
  • dc.date.available 2013-06-13T12:01:53Z
  • dc.date.issued 2012ca
  • dc.description.abstract 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 α(M)β(2)-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) (Fibγ(390-396A)) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the α(M)β(2) binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/α(M)β(2) 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)-α(M)β(2) interactions may provide a novel strategy for DMD treatment.
  • dc.description.sponsorship This work was supported by the European Commission, Seventh Framework Programme (Myoage, Optistem and Endostem)
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janué A, Flick MJ et al. Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor. Hum Mol Genet. 2012;21(9):1989-2004. DOI 10.1093/hmg/dds012ca
  • dc.identifier.doi http://dx.doi.org/10.1093/hmg/dds012
  • dc.identifier.issn 0964-6906ca
  • dc.identifier.uri http://hdl.handle.net/10230/20684
  • dc.language.iso engca
  • dc.publisher Oxford University Pressca
  • dc.relation.ispartof Human Molecular Genetics. 2012;21(9):1989-2004
  • dc.relation.ispartof Human Molecular Genetics. 2012;21(9):1989-2004
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/241440
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/223098
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/223576
  • dc.rights © Oxford University Press. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version 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 αMβ2 leukocyte integrin receptor. Hum Mol Genet. 2012; 21(9): 1989-2004 is available online at: http://dx.doi.org/10.1093/hmg/dds012ca
  • dc.rights.accessRights info:eu-repo/semantics/openAccessca
  • dc.subject.other Distròfia muscular de Duchenne -- Tractament
  • dc.subject.other Fibrina -- Metabolisme
  • dc.title Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptorca
  • dc.type info:eu-repo/semantics/articleca
  • dc.type.version info:eu-repo/semantics/acceptedVersionca

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