title: Fibroblasts from the muscles of Duchenne muscular dystrophy patients are resistant to cell detachment apoptosis.
abstract: Extracellular matrix (ECM) proteins, including collagen and growth factors, are greatly increased in tissue fibrosis and mainly secreted by fibroblasts. We previously demonstrated that muscle-derived fibroblasts from Duchenne muscular dystrophy (DMD) patients have a profibrotic phenotype, that includes significantly reduced expression of tissue inhibitor of metalloprotease 3 (TIMP-3) compared to control. Since TIMP-3 induces apoptosis in various cell types, we hypothesized increased resistance of DMD fibroblasts to apoptosis. To address this, we evaluated apoptotic nuclei, caspase 3, caspase 3 substrate expression, and migration and adhesion properties of muscle-derived fibroblasts, after applying different apoptosis-inducing treatments. We found that DMD fibroblasts were less susceptible to cell death, more adhesive, and had greater tendency to migrate than control fibroblasts - findings further supported by alterations in FAK and ERK/MAPK expression. Resistance to apoptosis and greater adhesion are likely to contribute to muscle fibrosis so a pharmacological treatment that targets dysregulated pathways involved in cell detachment apoptosis (anoikis) may limit the progressive fibrotic remodeling characteristic of DMD.
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation Neurological Institute C. Besta, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zanotti
authors.forename: S
authors.initials: S
authors.lastname: Gibertini
authors.forename: C
authors.initials: C
authors.lastname: Bragato
authors.forename: R
authors.initials: R
authors.lastname: Mantegazza
authors.forename: L
authors.initials: L
authors.lastname: Morandi
authors.forename: M
authors.initials: M
authors.lastname: Mora
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D007223:Infant; D018482:Muscle, Skeletal / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis / Q000473:pathology*