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Published on: August 3, 2018

Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway

Berta Vidal1, Antonio L Serrano, Marc Tjwa

  • 1Program on Differentiation and Cancer, Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), E-08003 Barcelona, Spain.

Genes & Development
|July 3, 2008
PubMed

Insights

Fibrinogen accumulation drives fibrosis in Duchenne muscular dystrophy (DMD). Reducing fibrinogen levels in mouse models of DMD lessened fibrosis and disease progression, highlighting fibrinogen as a therapeutic target for DMD.

Area of Science:

  • Muscle biology
  • Fibrosis research
  • Duchenne muscular dystrophy (DMD)

Background:

  • Duchenne muscular dystrophy (DMD) is a fatal degenerative disease characterized by progressive skeletal muscle replacement with fibrotic tissue.
  • The molecular mechanisms driving fibrosis in DMD are not fully understood.
  • Identifying key contributors to fibrosis is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of fibrinogen in the pathogenesis of Duchenne muscular dystrophy (DMD).
  • To elucidate the mechanisms by which fibrinogen contributes to muscle fibrosis.
  • To assess the therapeutic potential of targeting fibrinogen in DMD.

Main Methods:

  • Quantification of fibrinogen deposition in dystrophic muscles of DMD patients and mdx mice.
  • Assessment of fibrosis and dystrophy progression in mdx mice with genetic or pharmacological fibrinogen depletion.
  • Analysis of molecular pathways involving fibrinogen, macrophages, fibroblasts, and cytokine signaling (IL-1beta, TGFbeta).

Main Results:

  • Fibrinogen was found to accumulate in the dystrophic muscles of DMD patients and mdx mice.
  • Genetic deletion or pharmacological depletion of fibrinogen significantly reduced fibrosis and slowed dystrophy progression in mdx mice.
  • Fibrinogen binding to Mac-1 on macrophages induced IL-1beta, stimulating TGFbeta synthesis, which promoted collagen production by fibroblasts.
  • Fibrinogen-derived TGFbeta further amplified collagen accumulation via alternatively activated macrophages.
  • Fibrinogen directly promoted fibroblast collagen synthesis through its alphavbeta3 receptor.

Conclusions:

  • Fibrinogen plays a significant profibrotic role in Duchenne muscular dystrophy (DMD).
  • Targeting fibrinogen deposition or its downstream signaling pathways presents a promising therapeutic strategy for mitigating fibrosis and slowing disease progression in DMD.
  • Understanding fibrinogen's multifaceted profibrotic actions provides new insights into DMD pathogenesis.

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