Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway.
Genes Dev
; 22(13): 1747-52, 2008 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-18593877
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fibrinogênio
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Fator de Crescimento Transformador beta
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Distrofia Muscular de Duchenne
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Ativação de Macrófagos
Limite:
Animals
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Child
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Child, preschool
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Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article