Fibrinogen Drives Dystrophic Muscle Fibrosis Via a TGFbeta/alternative Macrophage Activation Pathway

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2008 Jul 3

PMID 18593877

Citations 146

Authors

Berta Vidal

Antonio L Serrano

Marc Tjwa

Monica Suelves

Esther Ardite

Roberta De Mori

Bernat Baeza-Raja

Maria Martinez de Lagran

Peggy Lafuste

Vanessa Ruiz-Bonilla

Merce Jardi

Romain Gherardi

Christo Christov

Mara Dierssen

Peter Carmeliet

Jay L Degen

Mieke Dewerchin

Pura Munoz-Canoves

Affiliations

Soon will be listed here.

Abstract

In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen-Mac-1 receptor binding, through induction of IL-1beta, drives the synthesis of transforming growth factor-beta (TGFbeta) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGFbeta further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its alphavbeta3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.

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