title: NF-κB inhibition reveals a novel role for HGF during skeletal muscle repair.
abstract: The transcription factor nuclear factor κB (NF-κB)/p65 is the master regulator of inflammation in Duchenne muscular dystrophy (DMD). Disease severity is reduced by NF-κB inhibition in the mdx mouse, a murine DMD model; however, therapeutic targeting of NF-κB remains problematic for patients because of its fundamental role in immunity. In this investigation, we found that the therapeutic effect of NF-κB blockade requires hepatocyte growth factor (HGF) production by myogenic cells. We found that deleting one allele of the NF-κB subunit p65 (p65+/-) improved the survival and enhanced the anti-inflammatory capacity of muscle-derived stem cells (MDSCs) following intramuscular transplantation. Factors secreted from p65+/- MDSCs in cell cultures modulated macrophage cytokine expression in an HGF-receptor-dependent manner. Indeed, we found that following genetic or pharmacologic inhibition of basal NF-κB/p65 activity, HGF gene transcription was induced in MDSCs. We investigated the role of HGF in anti-NF-κB therapy in vivo using mdx;p65+/- mice, and found that accelerated regeneration coincided with HGF upregulation in the skeletal muscle. This anti-NF-κB-mediated dystrophic phenotype was reversed by blocking de novo HGF production by myogenic cells following disease onset. HGF silencing resulted in increased inflammation and extensive necrosis of the diaphragm muscle. Proteolytic processing of matrix-associated HGF is known to activate muscle stem cells at the earliest stages of repair, but our results indicate that the production of a second pool of HGF by myogenic cells, negatively regulated by NF-κB/p65, is crucial for inflammation resolution and the completion of repair in dystrophic skeletal muscle. Our findings warrant further investigation into the potential of HGF mimetics for the treatment of DMD.
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Proto
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lu
authors.affiliation: 1] Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: W C W
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Stahl
authors.affiliation: 1] Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Poddar
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Beckman
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL.
authors.forename: P D
authors.initials: PD
authors.lastname: Robbins
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL.
authors.forename: L J
authors.initials: LJ
authors.lastname: Nidernhofer
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Imbrogno
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hannigan
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Mars
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Huard
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000502:physiology*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: C553307:HGF protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D017228:Hepatocyte Growth Factor