TGF-β-induced fibrosis and SMAD signaling:: oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring
TGF-β-induced fibrosis and SMAD signaling:: oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring
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DOI：
10.1111/j.1524-475x.2007.00226.x
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发表时间：
2007-09-01
影响因子：
2.9
通讯作者：
Cutroneo, Kenneth R.
中科院分区：
文献类型：
--
作者：
Cutroneo, Kenneth R.
转化生长因子-β（TGF-β）是一种由体内许多细胞合成的多效性生长因子。这种生长因子对成纤维细胞具有趋化性，刺激成纤维细胞增殖，并增加许多细胞外基质蛋白（包括胶原蛋白）的合成。TGF-β激活蛋白是一种反式作用因子，其与COL 1A 1胶原基因远端启动子中的TGF-β元件结合并诱导该基因的转录。虽然短暂的TGF-β 1活性参与组织的修复和再生，但持续的TGF-β 1功能会影响过度的纤维化，并最终导致皮肤和内脏的瘢痕形成。内部器官瘢痕（例如，肝和肺）导致功能丧失并最终可能发生死亡。这篇评论的中心问题是，硫代磷酸双链诱饵或其他诱饵减少前胶原基因表达，前胶原合成，和胶原纤维形成过程中。基本原理是含有TGF-β元件或其他基因转录调节CIS元件的诱饵结合反式作用蛋白，防止后者结合天然基因的5 '侧翼区中的CIS元件，导致转录抑制。我们将部分关注TGF-β 1诱导的纤维化发生过程中所涉及的方面，以及使用含有dsTGF-β元件的寡脱氧核苷酸诱饵来控制过度的胶原蛋白合成和持续性TGF-β导致的沉积。在我们的胶原合成调控模型中，这些双链寡诱饵作为启动子竞争者，与细胞质或细胞核中的激活蛋白结合。所提出的研究的意义在于，这些新型天然抗纤维化药物将模拟糖皮质激素在纤维发生期间对胶原蛋白合成的作用，而没有这些类固醇的不良副作用。基于我们先前对糖皮质激素选择性降低胶原合成的分子机制的研究，设计的抗核酸酶作用的硫代磷酸寡脱氧核苷酸将在分子、细胞和体内胶原合成水平上模拟糖皮质激素的作用。然而，糖皮质激素显着抑制非胶原蛋白的合成。单链和双链寡脱氧核苷酸都特异性地减少胶原蛋白的合成，而对非胶原蛋白的合成没有抑制作用。在这篇综述中，我们将特别问，如果TGF-β诱导的胶原蛋白合成抑制在细胞培养和体内使用的双链寡脱氧核苷酸诱饵，这将抑制纤维化，并最终疤痕？
Transforming-growth factor-beta (TGF-beta) is a pleiotrophic growth factor that is synthesized by many cells in the body. This growth factor is chemotactic for fibroblasts, stimulates fibroblast proliferation, and increases the synthesis of a number of extracellular matrix proteins including collagens. The TGF-beta activator protein is a transacting factor, which binds to the TGF-beta element in the distal promoter of the COL1A1 collagen gene and induces transcription of this gene. Although transient TGF-beta 1 activity participates in repair and regeneration of tissues, persistent TGF-beta 1 function affects excessive fibrosis and ultimately scarring of both skin and internal organs. Scarring of internal organ (e.g., liver and lung) results in a loss of function and ultimately death may occur. The central issue of this review is that phosphorothioate double-stranded decoys or other decoys decrease procollagen gene expression, procollagen synthesis, and collagen during fibrogenesis. The rationale is that the decoys containing the TGF-beta element or other gene transcription regulatory CIS-elements bind the transacting proteins preventing the latter from binding to the CIS-element in the 5'-flanking region of the natural gene resulting in transcription inhibition. We will, in part, focus on aspects involved in TGF-beta 1-induced fibrosis that occur during fibrogenesis and the use of the dsTGF-beta element containing oligodeoxynucleotide decoys to control excessive collagen synthesis, and deposition resulting from persistent TGF-beta. In our model of regulation of collagen synthesis, these double-stranded oligo decoys act as promoter competitors, binding to the activator protein either in the cytoplasm or in the nucleus. The significance of the proposed studies is that these novel natural antifibrotics will mimic the effect of glucocorticoids on collagen synthesis during fibrogenesis without the unwanted side effects of these steroids. Based on our previous studies on the molecular mechanisms by which glucocorticoids selectively decrease collagen synthesis, designed phosphorothioate oligodeoxynucleotides resistant to nuclease action will mimic the effects of glucocorticoids at the molecular, cellular, and in vivo levels of collagen synthesis. However, the glucocorticoids significantly inhibit noncollagen protein synthesis. Both the single-stranded and double-stranded oligodeoxynucleotide specifically decrease collagen synthesis without an inhibitory effect on noncollagen protein synthesis. In this review, we will specifically ask if TGF-beta-induced collagen synthesis is inhibited in cell culture and in vivo by using the double-stranded oligodeoxynucleotide decoys, will this inhibit fibrogenesis and ultimately scarring?