Constitutively activated dystrophic muscle fibroblasts show a paradoxical response to TGF-β and CTGF/CCN2
Constitutively activated dystrophic muscle fibroblasts show a paradoxical response to TGF-β and CTGF/CCN2
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DOI：
10.1007/s12079-008-0018-2
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发表时间：
2007-12-01
影响因子：
4.1
通讯作者：
Brandan, Enrique
中科院分区：
文献类型：
--
作者：
Mezzano, Valeria;Cabrera, Daniel;Brandan, Enrique
转化生长因子β(TGF-β)和结缔组织生长因子(CTGF)被认为可诱导细胞外基质(ECM)蛋白的产生，并在不同的纤维化疾病中被报道增加。骨骼肌纤维化是Duchenne肌营养不良症(DMD)的常见特征。MDX小鼠横隔膜是研究DMD的一个很好的模型，因为它复制了肌肉的退行性和纤维性改变。纤维连接蛋白(FN)和蛋白多糖(PG)是营养不良条件下上调的一些细胞外基质蛋白。为了了解DMD所涉及的纤维化过程，我们从营养不良的MDX横隔膜中分离出成纤维细胞。在这里，我们报告，无论没有退行性肌纤维，成人MDX横隔膜成纤维细胞显示增加水平的纤维连接蛋白和软骨素/硫酸皮肤素PGs合成。从非纤维性组织分离的成纤维细胞，如1周大的小鼠横隔膜或皮肤，不存在Fn水平升高。此外，MDX成纤维细胞条件培养液还能刺激对照成纤维细胞合成FN。MDX细胞自分泌转化生长因子-β信号未发生改变。当对照组成纤维细胞暴露于转化生长因子β和结缔组织生长因子时，纤维连接蛋白如预期的那样增加。矛盾的是，在MDX细胞中，它以浓度依赖的方式减少，这种减少并不是由于FN合成的下调。根据这些数据，我们假设病理环境能够将成纤维细胞重新编程为激活的表型，这种表型可以代代相传。
Transforming growth factor beta (TGF-beta) and connective tissue growth factor (CTGF) have been described to induce the production of extracellular matrix (ECM) proteins and have been reported to be increased in different fibrotic disorders. Skeletal muscle fibrosis is a common feature of Duchenne muscular dystrophy (DMD). The mdx mouse diaphragm is a good model for DMD since it reproduces the muscle degenerative and fibrotic changes. Fibronectin (FN) and proteoglycans (PG) are some of the ECM proteins upregulated in dystrophic conditions. In view of understanding the fibrotic process involved in DMD we have isolated fibroblasts from dystrophic mdx diaphragms. Here we report that regardless of the absence of degenerative myofibers, adult mdx diaphragm fibroblasts show increased levels of FN and condroitin/dermatan sulfate PGs synthesis. Fibroblasts isolated from non fibrotic tissue, such as 1 week old mice diaphragms or skin, do not present elevated FN levels. Furthermore, mdx fibroblast conditioned media is able to stimulate FN synthesis in control fibroblasts. Autocrine TGF-beta signaling was unaltered in mdx cells. When control fibroblasts are exposed to TGF-beta and CTGF, FN increases as expected. Paradoxically, in mdx cells it decreases in a concentration dependent manner and this decrease is not due to a downregulation of FN synthesis. According to this data we hypothesize that a pathological environment is able to reprogram fibroblasts into an activated phenotype which can be maintained through generations.