Connective tissue growth factor causes persistent proalpha2(I) collagen gene expression induced by transforming growth factor-beta in a mouse fibrosis model.
Connective tissue growth factor causes persistent proalpha2(I) collagen gene expression induced by transforming growth factor-beta in a mouse fibrosis model.
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发表时间：
2005
影响因子：
5.6
通讯作者：
Sonoko Chujo;F. Shirasaki;S. Kawara;Y. Inagaki;Takuro Kinbara;M. Inaoki;M. Takigawa;K. Takehara
中科院分区：
文献类型：
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作者：
Sonoko Chujo;F. Shirasaki;S. Kawara;Y. Inagaki;Takuro Kinbara;M. Inaoki;M. Takigawa;K. Takehara
皮肤纤维化疾病如系统性硬化症（SSc）的特点是细胞外基质（ECM）的过量产生，并在某些生长因子的影响下发展。结缔组织生长因子（CTGF）是一种富含半胱氨酸的有丝分裂肽，与各种纤维化疾病有关，并在转化生长因子- β (tgf - β)激活后诱导成纤维细胞。为了更好地理解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短暂性诱导皮下纤维化，tgf - β引起持续性纤维化后连续注射CTGF。为了进一步明确tgf - β和CTGF在体内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proalpha2 (I)胶原（COL1A2）基因启动子活性的影响。为此，我们利用转基因报告小鼠携带小鼠COL1A2的- 17kb启动子序列，该序列与萤火虫荧光素酶基因或细菌β -半乳糖苷酶基因相连。与单独连续注射tgf - β相比，在tgf - β后连续注射CTGF可在第8天持续升高COL1A2 mRNA表达和启动子活性。我们还证明，与单独注射tgf - β相比，在tgf - β后连续注射CTGF可增加COL1A2转录活化的成纤维细胞的数量。此外，连续注射可招募肥大细胞和巨噬细胞。肥大细胞数量在第4天达到最大值，一直保持到第8天。与肥大细胞的动力学相反，巨噬细胞的数量在第4天增加，并在随后连续注射CTGF至第8天期间继续增加。这些结果表明，CTGF通过维持COL1A2启动子激活和增加活化的成纤维细胞数量来维持tgf - β诱导的皮肤纤维化。浸润的肥大细胞和巨噬细胞也可能参与纤维化的维持。
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 proalpha2 (I) 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 beta-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.