Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy
Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy
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DOI：
10.1093/hmg/ddt352
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发表时间：
2013-12-15
影响因子：
3.5
通讯作者：
Brandan, Enrique
中科院分区：
文献类型：
--
作者：
Gabriela Morales, Maria;Gutierrez, Jaime;Brandan, Enrique
在Duchenne肌营养不良症（DMD）和mdx小鼠模型中，细胞骨架蛋白肌营养不良蛋白的缺乏导致肌纤维与基底层的锚定缺陷。由此产生的肌纤维变性和坏死导致肌肉质量的进行性损失、纤维化增加和最终致命的虚弱。结缔组织生长因子（CTGF/CCN-2）在多种慢性纤维变性疾病中起重要作用。在DMD中，CTGF的作用可能远远超出继发于肌纤维损失的替代性纤维化，因为其在骨骼肌中的过度表达本身可诱导营养不良表型。使用两种独立的方法，我们在这里表明，CTGF可用性降低的mdx小鼠确实具有较轻的肌营养不良症。具有半合子CTGF缺失的Mdx小鼠（mdx-Ctgf+/-）和用中和性抗CTGF单克隆抗体（FG-3019）处理的mdx小鼠在运动耐力测试中表现更好，在分离的肌肉中具有更好的肌肉强度并且减少骨骼肌损伤、凋亡损伤和纤维化。在CTGF抑制过程中，转化生长因子β（TGF-β）、pERK 1/2和p38信号传导不受影响。此外，mdx-Ctgf+/-和FG-3019处理的mdx小鼠在肌内注射肌营养不良蛋白阳性卫星细胞后均具有改善的移植。这些发现揭示了靶向CTGF以减少疾病进展和改善DMD细胞治疗的潜力。
In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-beta (TGF-beta), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.