期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 27, 页码 10978-10983出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1204708109
关键词
collagen; transgenic mice; dystrophin-glycoprotein complex; paracrine
资金
- National Institutes of Health
- Howard Hughes Medical Institute
- Physician Scientist Award Pediatric Center Grant from the Institute of Child Health and Human Development
The muscular dystrophies are broadly classified as muscle wasting diseases with myofiber dropout due to cellular necrosis, inflammation, alterations in extracellular matrix composition, and fatty cell replacement. These events transpire and progress despite ongoing myofiber regeneration from endogenous satellite cells. The degeneration/regeneration response to muscle injury/disease is modulated by the proinflammatory cytokine transforming growth factor-beta (TGF-beta), which can also profoundly influence extracellular matrix composition through increased secretion of profibrotic proteins, such as the matricellular protein periostin. Here we show that up-regulation and secretion of periostin is pathological and enhances disease in the delta-sarcoglycan null (Sgcd(-/-)) mouse model of muscular dystrophy (MD). Indeed, MD mice lacking the Postn gene showed dramatic improvement in skeletal muscle structure and function. Mechanistically, Postn gene deletion altered TGF-beta signaling so that it now enhanced tissue regeneration with reduced levels of fibrosis. Systemic antagonism of TGF-beta with a neutralizing monoclonal antibody mitigated the beneficial effects of Postn deletion in vivo. These data suggest that periostin functions as a disease determinant in MD by promoting/allowing the pathological effects of TGF-beta, suggesting that inhibition of periostin could represent a unique treatment approach.
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