Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy

Maria Gabriela Morales, Jaime Gutierrez, Claudio Cabello-Verrugio, Daniel Cabrera, Kenneth E. Lipson, Roel Goldschmeding, Enrique Brandan

Resultado de la investigación: Article

65 Citas (Scopus)

Resumen

In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.

Idioma originalEnglish
Número de artículoddt352
Páginas (desde-hasta)4938-4951
Número de páginas14
PublicaciónHuman Molecular Genetics
Volumen22
N.º24
DOI
EstadoPublished - 1 dic 2013

Huella dactilar

Inbred mdx Mouse
Cell- and Tissue-Based Therapy
Duchenne Muscular Dystrophy
Muscles
Dystrophin
Fibrosis
Skeletal Muscle
Connective Tissue Growth Factor
Cytoskeletal Proteins
Muscular Dystrophies
Intramuscular Injections
Muscle Strength
Transforming Growth Factors
Exercise Test
Basement Membrane
Disease Progression
Necrosis
Monoclonal Antibodies
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Citar esto

Morales, M. G., Gutierrez, J., Cabello-Verrugio, C., Cabrera, D., Lipson, K. E., Goldschmeding, R., & Brandan, E. (2013). Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy. Human Molecular Genetics, 22(24), 4938-4951. [ddt352]. https://doi.org/10.1093/hmg/ddt352
Morales, Maria Gabriela ; Gutierrez, Jaime ; Cabello-Verrugio, Claudio ; Cabrera, Daniel ; Lipson, Kenneth E. ; Goldschmeding, Roel ; Brandan, Enrique. / Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy. En: Human Molecular Genetics. 2013 ; Vol. 22, N.º 24. pp. 4938-4951.
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abstract = "In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.",
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Morales, MG, Gutierrez, J, Cabello-Verrugio, C, Cabrera, D, Lipson, KE, Goldschmeding, R & Brandan, E 2013, 'Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy', Human Molecular Genetics, vol. 22, n.º 24, ddt352, pp. 4938-4951. https://doi.org/10.1093/hmg/ddt352

Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy. / Morales, Maria Gabriela; Gutierrez, Jaime; Cabello-Verrugio, Claudio; Cabrera, Daniel; Lipson, Kenneth E.; Goldschmeding, Roel; Brandan, Enrique.

En: Human Molecular Genetics, Vol. 22, N.º 24, ddt352, 01.12.2013, p. 4938-4951.

Resultado de la investigación: Article

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T1 - Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy

AU - Morales, Maria Gabriela

AU - Gutierrez, Jaime

AU - Cabello-Verrugio, Claudio

AU - Cabrera, Daniel

AU - Lipson, Kenneth E.

AU - Goldschmeding, Roel

AU - Brandan, Enrique

PY - 2013/12/1

Y1 - 2013/12/1

N2 - In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.

AB - In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.

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DO - 10.1093/hmg/ddt352

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Morales MG, Gutierrez J, Cabello-Verrugio C, Cabrera D, Lipson KE, Goldschmeding R y otros. Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy. Human Molecular Genetics. 2013 dic 1;22(24):4938-4951. ddt352. https://doi.org/10.1093/hmg/ddt352