Immunomodulation of TGF-beta 1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy.
Irreversible connective tissue proliferation in muscle is a pathological hallmark of Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease due to lack of the sarcolemmal protein dystrophin. Focal release of transforming growth factor-beta1 (TGF-beta1) is involved in fibrosis development. Murine muscular dystrophy (mdx) is genetically homologous to DMD and histopathological alterations comparable to those in DMD muscles occur in diaphragm of older mdx mice. To investigate the early development of fibrosis and TGF-beta1 involvement, we assessed diaphragms in 6-36-week-old mdx and C57/BL6 (control) mice for fibrosis, and used real-time PCR and ELISA to determine TGF-beta1 expression. Significantly greater fibrosis and TGF-beta1 expression were found in mdx from the 6th week. Mice treated with neutralizing antibody against TGF-beta1 had lower levels of TGF-beta1 protein, reduced fibrosis, unchanged muscles fiber degeneration/regeneration, but increased inflammatory cells (CD4+lymphocytes). These data demonstrate early and progressive fibrosis in mdx diaphragm accompanied by TGF-beta1 upregulation. Reduction of TGF-beta1 appears promising as a therapeutic approach to muscle fibrosis, but further studies are required to evaluate long term effects of TGF-beta1 immunomodulation on the immune system.
Andreetta
Francesca
F
Department of Neuroimmunology and Neuromuscular Diseases, National Neurological Institute Carlo Besta, via Celoria 11, 20133 Milan, Italy.
Bernasconi
Pia
P
Baggi
Fulvio
F
Ferro
Paolo
P
Oliva
Laura
L
Arnoldi
Elisa
E
Cornelio
Ferdinando
F
Mantegazza
Renato
R
Confalonieri
Paolo
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D049109:Cell Proliferation; D003238:Connective Tissue / Q000276:immunology* / Q000473:pathology*; D003964:Diaphragm / Q000276:immunology* / Q000473:pathology*; D005355:Fibrosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000276:immunology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use; D007155:Immunologic Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology*; D053773:Transforming Growth Factor beta1
D000911:Antibodies, Monoclonal; D006131:Growth Inhibitors; D007074:Immunoglobulin G; D007155:Immunologic Factors; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1