BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model
BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model
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DOI：
10.1016/j.nbd.2010.10.003
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发表时间：
2011-02-01
影响因子：
6.1
通讯作者：
't Hoen, Peter A. C.
中科院分区：
文献类型：
--
作者：
Shi, SongTing;Hoogaars, Willem M. H.;'t Hoen, Peter A. C.
杜氏肌营养不良症（DMD）是一种以肌纤维变性和坏死为特征的X连锁致死性肌肉萎缩性疾病。DMD的进行性病理学可以通过导致纤维化和脂肪组织形成的再生反应不足来解释。已知BMP抑制肌源性分化，并且在先前的研究中，我们发现BMP家族成员BMP 4在DMD成肌细胞中的表达增加。因此，本研究的目的是研究在DMD背景下抑制BMP信号传导是否有利于成肌细胞分化和肌肉再生过程。所有测试的BMP抑制剂，头蛋白，dorsomorphin和LDN-193189，能够加速和增强肌原性分化。然而，dorsomorphin抑制BMP和TG β信号传导，并被发现对原代成肌细胞培养物有毒。相比之下，发现Noggin是一种有效的选择性BMP抑制剂，因此在DMD小鼠模型中进行了体内测试。局部腺病毒介导的Noggin在肌肉中的过表达导致肌生成调节基因Myog和Myod 1的表达增加，并改善肌肉组织学。总之，我们的研究结果表明，BMP信号的抑制可能构成一个有吸引力的治疗DMD患者。(C)2010年爱思唯尔公司All rights reserved.
Duchenne Muscular Dystrophy (DMD) is an X-linked lethal muscle wasting disease characterized by muscle fiber degeneration and necrosis. The progressive pathology of DMD can be explained by an insufficient regenerative response resulting in fibrosis and adipose tissue formation. BMPs are known to inhibit myogenic differentiation and in a previous study we found an increased expression of a BMP family member BMP4 in DMD myoblasts. The aim of the current study was therefore to investigate whether inhibition of BMP signaling could be beneficial for myoblast differentiation and muscle regeneration processes in a DMD context. All tested BMP inhibitors, Noggin, dorsomorphin and LDN-193189, were able to accelerate and enhance myogenic differentiation. However, dorsomorphin repressed both BMP and TG beta signaling and was found to be toxic to primary myoblast cell cultures. In contrast, Noggin was found to be a potent and selective BMP inhibitor and was therefore tested in vivo in a DMD mouse model. Local adenoviral-mediated overexpression of Noggin in muscle resulted in an increased expression of the myogenic regulatory genes Myog and Myod1 and improved muscle histology. In conclusion, our results suggest that repression of BMP signaling may constitute an attractive adjunctive therapy for DMD patients. (C) 2010 Elsevier Inc. All rights reserved.