RESUMEN
Muscular dystrophies are genetic conditions leading to muscle degeneration and often, impaired regeneration. Duchenne Muscular Dystrophy is a prototypical form of muscular dystrophy, and like other forms of genetically inherited muscle diseases, pathological progression is variable. Variability in muscular dystrophy can arise from differences in the manner in which the primary mutation impacts the affected protein's function; however, clinical heterogeneity also derives from secondary mutations in other genes that can enhance or reduce pathogenic features of disease. These genes, called genetic modifiers, regulate the pathophysiological context of dystrophic degeneration and regeneration. Understanding the mechanistic links between genetic modifiers and dystrophic progression sheds light on pathologic remodeling, and provides novel avenues to therapeutically intervene to reduce muscle degeneration. Based on targeted genetic approaches and unbiased genomewide screens, several modifiers have been identified for muscular dystrophy, including extracellular agonists of signaling cascades. This review will focus on identification and possible mechanisms of recently identified modifiers for muscular dystrophy, including osteopontin, latent TGFß binding protein 4 (LTBP4) and Jagged1. Moreover, we will review the investigational approaches that aim to target modifier pathways and thereby counteract dystrophic muscle wasting.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Proteína Jagged-1/genética , Proteínas de Unión a TGF-beta Latente/genética , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Osteopontina/genética , Animales , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Drogas en Investigación/uso terapéutico , Marcadores Genéticos , Humanos , Proteína Jagged-1/agonistas , Proteína Jagged-1/metabolismo , Proteínas de Unión a TGF-beta Latente/agonistas , Proteínas de Unión a TGF-beta Latente/metabolismo , Terapia Molecular Dirigida , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Osteopontina/antagonistas & inhibidores , Osteopontina/metabolismo , Índice de Severidad de la Enfermedad , Transducción de SeñalRESUMEN
Latent TGF-beta (LTGF-beta) has to be converted to active TGF-beta for its activities. Previously, we reported that certain fragments of latency associated peptide (LAP) augmented LTGF-beta activation via increase in binding of LTGF-beta to the endothelial cell (EC) surface followed by cell-associated proteolysis. By searching for EC membrane proteins crosslinked with the LAP fragment, we identified the molecule bound to LAP fragment as vimentin. Moreover, the LAP fragment-induced LTGF-beta activation was attenuated by anti-vimentin antibody. These results indicate that binding of the LAP fragment to vimentin on the cell surface is indispensable for LTGF-beta activation by the LAP fragment.