Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

Angela Lorts, Jennifer A. Schwanekamp, Troy A. Baudino, Elizabeth M. McNally, Jeffery D. Molkentin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

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-β (TGF-β), 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 δ-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-β signaling so that it now enhanced tissue regeneration with reduced levels of fibrosis. Systemic antagonism of TGF-β 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-β, suggesting that inhibition of periostin could represent a unique treatment approach.

Original languageEnglish (US)
Pages (from-to)10978-10983
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number27
DOIs
StatePublished - Jul 3 2012

Keywords

  • Collagen
  • Dystrophin-glycoprotein complex
  • Paracrine
  • Transgenic mice

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway'. Together they form a unique fingerprint.

Cite this