Targeting latent TGFβ release in muscular dystrophy

Ermelinda Ceco, Sasha Bogdanovich, Brandon Gardner, Tamari Miller, Adam DeJesus, Judy U. Earley, Michele Hadhazy, Lucas R. Smith, Elisabeth R. Barton, Jeffery D. Molkentin, Elizabeth M. McNally

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGFβ signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGFβ release and activity and decrease inflammation and muscle damage in muscular dystrophy.

Original languageEnglish (US)
Pages (from-to)259ra144
JournalScience Translational Medicine
Volume6
Issue number259
DOIs
StatePublished - Oct 22 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Ceco, E., Bogdanovich, S., Gardner, B., Miller, T., DeJesus, A., Earley, J. U., Hadhazy, M., Smith, L. R., Barton, E. R., Molkentin, J. D., & McNally, E. M. (2014). Targeting latent TGFβ release in muscular dystrophy. Science Translational Medicine, 6(259), 259ra144. https://doi.org/10.1126/scitranslmed.3010018