RESUMEN
Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-ß (TGFß) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFß induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFß on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFß-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFß signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.
Asunto(s)
Autofagia/genética , Epigénesis Genética , Histona Acetiltransferasas/metabolismo , Esclerodermia Sistémica/patología , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Anciano , Animales , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Biopsia , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Fibroblastos , Fibrosis , Técnicas de Inactivación de Genes , Voluntarios Sanos , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Células 3T3 NIH , Cultivo Primario de Células , Receptores de Factores de Crecimiento Transformadores beta , Transducción de Señal/genética , Piel/citología , Piel/patología , Proteína smad3/metabolismo , Adulto JovenRESUMEN
Autophagy describes the degradation of unnecessary or dysfunctional cellular components through the lysosomal machinery. Autophagy is essentially required to prevent accumulation of cellular damage and to ensure cellular homeostasis. Indeed, impaired autophagy has been implicated in a variety of different diseases. We examined the role of autophagy in inflammatory bone loss. We demonstrated that autophagy is activated by the pro-inflammatory cytokine tumor necrosis factor (TNF/TNFα) in osteoclasts of patients with rheumatoid arthritis (RA). Autophagy induces osteoclast differentiation and stimulates osteoclast-mediated bone resorption in vitro and in vivo, thereby highlighting autophagy as a novel mediator of TNF-induced bone resorption.