Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers
Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers
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DOI：
10.1093/hmg/ddr062
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发表时间：
2011-05-01
影响因子：
3.5
通讯作者：
Ikeda, Shu-ichi
中科院分区：
文献类型：
--
作者：
Miyazaki, Daigo;Nakamura, Akinori;Ikeda, Shu-ichi
基质金属蛋白酶（MMP）是一个内肽酶家族，根据正常生理过程（如胚胎发育和组织重塑）以及通过降解细胞外基质组分的各种疾病过程中的底物偏好分为亚组。在MMP中，MMP-9和MMP-2已被报道在致死性X连锁肌肉疾病杜氏肌营养不良症（DMD）中的骨骼肌中上调，所述杜氏肌营养不良症是由肌营养不良蛋白的缺失引起的。最近的一项研究表明，MMP 9基因在mdx（DMD的小鼠模型）中的缺失改善了骨骼肌的病理学和功能;然而，MMP-2在肌营养不良蛋白缺陷型肌肉中的作用尚不清楚。在这项研究中，我们的目的是验证MMP-2在肌营养不良蛋白缺乏的肌肉中的作用，通过使用基因消融MMP-2的mdx小鼠（mdx/MMP-2（-/-））。我们发现mdx/MMP-2（-/-）小鼠在3月龄时再生肌纤维生长受损，血管生成减少。mdx/MMP-2（-/-）小鼠在3月龄时血管内皮生长因子-A（VEGF-A）的表达降低，VEGF-A是一种重要的血管生成相关因子。MMP-2在肌营养不良蛋白-糖蛋白复合物（DGC）组分如β-肌营养不良蛋白聚糖和β-肌聚糖的降解中没有关键作用。因此，MMP-2可能是通过VEGF相关的血管生成在肌营养不良蛋白缺陷的骨骼肌再生肌纤维的生长所必需的。
Matrix metalloproteases (MMPs) are a family of endopeptidases classified into subgroups based on substrate preference in normal physiological processes such as embryonic development and tissue remodeling, as well as in various disease processes via degradation of extracellular matrix components. Among the MMPs, MMP-9 and MMP-2 have been reported to be up-regulated in skeletal muscles in the lethal X-linked muscle disorder Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. A recent study showed that deletion of the MMP9 gene in mdx, a mouse model for DMD, improved skeletal muscle pathology and function; however, the role of MMP-2 in the dystrophin-deficient muscle is not well known. In this study, we aimed at verifying the role of MMP-2 in the dystrophin-deficient muscle by using mdx mice with genetic ablation of MMP-2 (mdx/MMP-2(-/-)). We found impairment of regenerated muscle fiber growth with reduction of angiogenesis in mdx/MMP-2(-/-) mice at 3 months of age. Expression of vascular endothelial growth factor-A (VEGF-A), an important angiogenesis-related factor, decreased in mdx/MMP-2(-/-) mice at 3 months of age. MMP-2 had not a critical role in the degradation of dystrophin-glycoprotein complex (DGC) components such as beta-dystroglycan and beta-sarcoglycan in the regeneration process of the dystrophic muscle. Accordingly, MMP-2 may be essential for growth of regenerated muscle fibers through VEGF-associated angiogenesis in the dystrophin-deficient skeletal muscle.