2013-06-19T20:31:44Zhttp://www.tdx.cat/oai/request

oai:www.tdx.cat:10803/71432012-07-27T10:46:06Zhdl_10803_237

am 3u dc2009-07-10Duchenne muscular dystrophy (DMD) is a fatal degenerative disorder of locomotor and respiratory muscles, in which myofibers are progressively replaced by non-muscular fibrotic tissue. Here, we show that fibrin/ogen accumulates in dystrophic muscles of DMD patients and of the mdx mouse model of DMD. Genetic loss or pharmacological depletion of fibrin/ogen in mdx mice attenuated muscular dystrophy progression and improved locomotor capacity. More importantly, fibrin/ogen depletion reduced fibrosis in mdx mouse diaphragm. Our data indicate that fibrin/ogen, through induction of IL-1 Ò, drives the synthesis of TGF Ò by mdx macrophages, which in turn, induces collagen production in mdx fibroblasts. Fibrin/ogen-produced TGF Ò further amplifies collagen accumulation through recruitment and activation of pro-fibrotic alternatively activated macrophages. Fibrin/ogen also stimulated collagen synthesis directly in mdx fibroblasts, via Ñv Ò3 integrin engagement. In addition, when analyzing a group of 39 DMD patients, fibrin/ogen accumulation in locomotor muscles was found associated with fibrosis and disease severity. These data unveil a novel role of fibrin/ogen in muscular dystrophy and, importantly, in the replacement of muscle by fibrotic tissue.application/pdfhttp://www.tdx.cat/TDX-0710109-132830http://hdl.handle.net/10803/7143enginflammationdystrophyfibrinogenUPAfibrosimúsculinflamaciódistròfiafibrinogenUPAmusclefibrosis616.7 - Patologia dels òrgans de la locomoció. Sistema locomotor i esquelèticThe fibrinolitys system in muscle regeneration and dystrophy