RESUMEN
Marfan syndrome (MFS) is a systemic disorder of the connective tissues caused by insufficient fibrillin-1 microfibril formation and can cause cardiac complications, emphysema, ocular lens dislocation, and severe periodontal disease. ADAMTSL6ß (A disintegrin-like metalloprotease domain with thrombospondin type I motifs-like 6ß) is a microfibril-associated extracellular matrix protein expressed in various connective tissues that has been implicated in fibrillin-1 microfibril assembly. We here report that ADAMTSL6ß plays an essential role in the development and regeneration of connective tissues. ADAMTSL6ß expression rescues microfibril disorder after periodontal ligament injury in an MFS mouse model through the promotion of fibrillin-1 microfibril assembly. In addition, improved fibrillin-1 assembly in MFS mice following the administration of ADAMTSL6ß attenuates the overactivation of TGF-ß signals associated with the increased release of active TGF-ß from disrupted fibrillin-1 microfibrils within periodontal ligaments. Our current data thus demonstrate the essential contribution of ADAMTSL6ß to fibrillin-1 microfibril formation. These findings also suggest a new therapeutic strategy for the treatment of MFS through ADAMTSL6ß-mediated fibrillin-1 microfibril assembly.
Asunto(s)
Proteínas de la Matriz Extracelular/genética , Síndrome de Marfan/metabolismo , Proteínas de Microfilamentos/química , Animales , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/fisiología , Fibrilina-1 , Fibrilinas , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunohistoquímica/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microfibrillas/patología , Modelos Genéticos , Proteínas Recombinantes/química , Diente/embriología , Factor de Crecimiento Transformador beta/metabolismo , Cicatrización de HeridasRESUMEN
It was found that the reaction of 1,2,3-selenadiazoles derived from cyclic ketones with olefins or dienes was markedly promoted by a catalytic amount of tributylstannyl radical, which was generated in situ from tributylstannyl hydride or allyltributylstannane and AIBN, to give the corresponding dihydroselenophenes in moderate to good yields. In contrast, when 1,2,3-selenadiazoles prepared from linear and aromatic ketones were used as substrates, the same reaction did not take place, and alkynes were formed as the sole product.