Connective tissue growth factor causes persistent proα2(l) collagen gene expression induced by transforming growth factor-β in a mouse fibrosis model
Connective tissue growth factor causes persistent proα2(l) collagen gene expression induced by transforming growth factor-β in a mouse fibrosis model
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DOI：
10.1002/jcp.20251
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发表时间：
2005-05-01
影响因子：
5.6
通讯作者：
Takehara, K
中科院分区：
文献类型：
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作者：
Chujo, S;Shirasaki, F;Takehara, K
系统性硬化症 (SSc) 等皮肤纤维化疾病的特征是细胞外基质 (ECM) 产生过多，并且被认为是在某些生长因子的影响下发生的。结缔组织生长因子 (CTGF) 是一种富含半胱氨酸的促有丝分裂肽，与各种纤维化疾病有关，并在用转化生长因子-β (TGF-β) 激活后在成纤维细胞中诱导。为了更好地了解 SSc 中持续纤维化的机制，我们之前建立了外源性应用生长因子诱导皮肤纤维化的动物模型。在该模型中，TGF-β短暂诱导皮下纤维化，并在TGF-β引起持续性纤维化后连续注射CTGF。为了进一步明确体内TGF-β和CTGF诱导皮肤纤维化的机制，我们在本研究中研究了生长因子对皮肤纤维化中pro alpha 2（1）胶原蛋白（COL1A2）基因启动子活性的影响。为此，我们利用转基因报告小鼠，其带有与萤火虫荧光素酶基因或细菌β-半乳糖苷酶基因连接的小鼠COL1A2的-17 kb启动子序列。与第8天单独注射TGF-β相比，在TGF-β之后连续注射CTGF导致COL1A2 mRNA表达和启动子活性持续升高。我们还证明，与单独注射TGF-β相比，在TGF-β之后连续注射CTGF增加了具有激活的COL1A2转录的成纤维细胞的数量。此外，连续注射招募了肥大细胞和巨噬细胞。肥大细胞的数量在第 4 天达到最大值，并在第 8 天保持相对较高的水平。与肥大细胞的动力学相反，巨噬细胞的数量在第 4 天增加，并在随后连续 CTGF 注射期间继续增加，直到第 8 天。这些结果表明，CTGF 通过维持 COL1A2 启动子激活和增加激活的细胞数量来维持 TGF-β 诱导的皮肤纤维化。 成纤维细胞。浸润的肥大细胞和巨噬细胞也可能有助于纤维化的维持。 (c) 2004 年 Wiley-Liss, Inc.
Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive production of extracellular matrix (ECM) and understood to develop under the influence of certain growth factors. Connective tissue growth factor (CTGF) is a cysteine-rich mitogenic peptide that is implicated in various fibrotic disorders and induced in fibroblasts after activation with transforming growth factor-beta (TGF-beta). To better understand the mechanisms of persistent fibrosis seen in SSc, we previously established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, TGF-beta transiently induced subcutaneous fibrosis and serial injections of CTGF after TGF-beta caused persistent fibrosis. To further define the mechanisms of skin fibrosis induced by TGF-beta and CTGF in vivo, we investigated in this study, the effects of growth factors on the promoter activity of the pro alpha 2 (1) collagen (COL1A2) gene in skin fibrosis. For this purpose, we utilized transgenic reporter mice harboring the -17 kb promoter sequence of the mouse COL1A2 linked to either a firefly luciferase gene or a bacterial P-galactosidase gene. Serial injections of CTGF after TGF-beta resulted in a sustained elevation of COL1A2 mRNA expression and promoter activity compared with consecutive injection of TGF-beta alone on day 8. We also demonstrated that the number of fibroblasts with activated COL1A2 transcription was increased by serial injections of CTGF after TGF-beta in comparison with the injection of TGF-beta alone. Furthermore, the serial injections recruited mast cells and macrophages. The number of mast cells reached a maximum on day 4 and remained relatively high up to day 8. In contrast to the kinetics of mast cells, the number of macrophages was increased on day 4 and continued to rise during the subsequent consecutive CTGF injections until day 8. These results suggested that CTGF maintains TGF-beta-induced skin fibrosis by sustaining COL1A2 promoter activation and increasing the number of activated fibroblasts. The infiltrated mast cells and macrophages may also contribute to the maintenance of fibrosis. (c) 2004 Wiley-Liss, Inc.