A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice
A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice
复制标题
DOI：
10.1093/hmg/11.3.263
复制
发表时间：
2002-02-01
影响因子：
3.5
通讯作者：
Andrade, FH
中科院分区：
文献类型：
--
作者：
Porter, JD;Khanna, S;Andrade, FH
肌营养不良蛋白的突变引起杜氏肌营养不良症（DMD），但缺乏肌营养不良蛋白并不一定会在所有肌肉、生命阶段和物种中引起坏死。利用DNA微阵列，我们在mdx小鼠中建立了营养不良症的分子特征，并有证据表明次要机制是发病的关键因素。我们使用可变性控制，充分的重复和严格的分析工具，包括微阵列的显著性分析来估计和管理假阳性率。在腿部肌肉中，我们发现了242个差异表达基因，其中约75%的基因在人类或动物营养不良症中未被报道过。数据为慢性炎症反应的许多组成部分的协调活动提供了证据，包括细胞因子和趋化因子信号，白细胞粘附和渗出，侵袭性细胞类型特异性标记和补体系统激活。RT-PCR和免疫印迹证实了选择性趋化因子上调，可能是营养不良肌肉炎症反应性质的关键决定因素。营养不良肌肉中分泌的磷酸化蛋白1（骨桥蛋白、骨桥蛋白）mRNA和蛋白的上调发现了炎症细胞和修复过程之间的一种新的联系。细胞外基质基因在mdx中上调至与DMD相似的水平。与DMD不同，mdx表现出很少的纤维化，数据表明，转录后阶段的胶原调节介导了DMD的广泛纤维化。综上所述，这些数据确定了DMD相对被忽视的方面，提出了新的治疗途径，并强调了全基因组分析在复杂疾病过程研究中的价值。
Mutations in dystrophin cause Duchenne muscular dystrophy (DMD), but absent dystrophin does not invariably cause necrosis in all muscles, life stages and species. Using DNA microarray, we established a molecular signature of dystrophinopathy in the mdx mouse, with evidence that secondary mechanisms are key contributors to pathogenesis. We used variability controls, adequate replicates and stringent analytic tools, including significance analysis of microarrays to estimate and manage false positive rates. In leg muscle, we identified 242 differentially expressed genes, >75% of which have not been previously reported as altered in human or animal dystrophies. Data provide evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Selective chemokine upregulation was confirmed by RT-PCR and immunoblot, and may be a key determinant of the nature of the inflammatory response in dystrophic muscle. Up-regulation of secreted phosphoprotein 1 (minopontin, osteopontin) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were up-regulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggest that collagen regulation at post-transcriptional stages mediates extensive fibrosis in DMD. Taken together, these data identify a relatively neglected aspect of DMD, suggest new treatment avenues, and highlight the value of genome-wide profiling in study of complex disease processes.