title: Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy.
abstract: Matrix metalloprotease (MMP)-9 is an endopeptidase associated with the pathogenesis of Duchenne muscular dystrophy (DMD). The precise function of MMP-9 in DMD has not been elucidated to date. We investigated the effect of genetic ablation of MMP-9 in the mdx mouse model (mdx/Mmp9(-/-)). At the early disease stage, the muscles of mdx/Mmp9(-/-) mice showed reduced necrosis and neutrophil invasion, accompanied by down-regulation of chemokine MIP-2. In addition, muscle regeneration was enhanced, which coincided with increased macrophage infiltration and upregulation of MCP-1, and resulted in increased muscle strength. The mdx/Mmp9(-/-) mice also displayed accelerated upregulation of osteopontin expression in skeletal muscle at the acute onset phase of dystrophy. However, at a later disease stage, the mice exhibited muscle growth impairment through altered expression of myogenic factors, and increased fibroadipose tissue. These results showed that MMP-9 might have multiple functions during disease progression. Therapy targeting MMP-9 may improve muscle pathology and function at the early disease stage, but continuous inhibition of this protein may result in the accumulation of fibroadipose tissues and reduced muscle strength at the late disease stage.
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shiba
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Miyazaki
authors.affiliation: Division of Laboratory Animal Research, Research Center for Human and Environmental Sciences, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yoshizawa
authors.affiliation: Intractable Disease Care Center, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Fukushima
authors.affiliation: Department of Cardiovascular Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiba
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Inaba
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira 187-8561, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira 187-8561, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koike
authors.affiliation: Intractable Disease Care Center, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Electronic address: anakamu@shinshu-u.ac.jp.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nakamura
keywords: Dystrophin; Fibrosis; MCP-1; MIP-2; MMP-9; Osteopontin