title: Targeting latent TGFβ release in muscular dystrophy.
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.
authors.affiliation: Committee on Cell Physiology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Ceco
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.affiliation: Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Gardner
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Tamari
authors.initials: T
authors.lastname: Miller
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: DeJesus
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Judy U
authors.initials: JU
authors.lastname: Earley
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Hadhazy
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lucas R
authors.initials: LR
authors.lastname: Smith
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Barton
authors.affiliation: Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, OH 45229, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. elizabeth.mcnally@northwestern.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000378:metabolism; D005355:Fibrosis; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy; D053779:Latent TGF-beta Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000473:pathology; D057057:Serine Proteases / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D019076:Transgenes
chemical_list: C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D051785:Smad Proteins; D057057:Serine Proteases