Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Shiba, Naoko¹  Miyazaki, Daigo²  Yoshizawa, Takahiro³  Fukushima, Kazuhiro⁴  Shiba, Yuji⁵  Inaba, Yuji¹  Imamura, Michihiro⁶  Takeda, Shin'ichi⁶  Koike, Kenichi¹  Nakamura, Akinori⁴ 

[1] Shinshu Univ, Sch Med, Dept Pediat, Matsumoto, Nagano 3908621, Japan

[2] Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano 3908621, Japan

[3] Shinshu Univ, Res Ctr Human & Environm Sci, Div Lab Anim Res, Matsumoto, Nagano 3908621, Japan

[4] Shinshu Univ Hosp, Intractable Dis Care Ctr, Matsumoto, Nagano 3908621, Japan

[5] Shinshu Univ, Sch Med, Dept Cardiovasc Med, Matsumoto, Nagano 3908621, Japan

[6] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mol Therapy, Kodaira, Tokyo 1878561, Japan

关键词: Dystrophin;    Fibrosis;    MMP-9;    MIP-2;    MCP-1;    Osteopontin;   

DOI  :  10.1016/j.bbadis.2015.07.008

来源: Elsevier

【 摘 要 】

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 downregulation 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. (C) 2015 Elsevier B.V. All rights reserved.

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