title: Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy.
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.
authors.affiliation: Laboratorio de Diferenciación Celular y Patología, Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Maria Gabriela
authors.initials: MG
authors.lastname: Morales
authors.forename: Jaime
authors.initials: J
authors.lastname: Gutierrez
authors.forename: Claudio
authors.initials: C
authors.lastname: Cabello-Verrugio
authors.forename: Daniel
authors.initials: D
authors.lastname: Cabrera
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics; D005838:Genotype; D006085:Graft Survival / Q000235:genetics; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D033581:Stem Cell Transplantation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases