Modulation of collagen I, III gene expression in disorders of connective tissue

结缔组织疾病中胶原蛋白 I、III 基因表达的调节

基本信息

批准号：
03670536
负责人：
TAKADA Koji
金额：
$ 1.34万
依托单位：
Kawasaki Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

To understand the modulation of collagen metabolism and collagen gene expression in physiological and pathological conditions of connective tissue, we investigated whether histamine, cyclosporin A, pentoxifylline and tumor necrosis factor alpha (TNF alpha) affect collagen synthesis and collagen degradation in cultured skin fibroblasts. Histamine (1-10 mug/ml) stimulated collagen synthesis at the pretranslational level, however cyclosporin A (10^<-8>-10^<-6>M) did not affect to collagen expression at the therapeutic concentrations. The mRNA levels of alpha_1(I) collagen and fibronectin were decreased in pentoxifylline-treated (10-100 mug/ml) fibroblasts. TNF inhibited collagen synthesis and collagen I, III, and fibronectin mRNA levels, and stimulated collagenase expression in normal and scleroderma fibroblasts, while collagen VI mRNA levels were unaltered. We also found that collagen VI expression in Werner's syndrome fibroblasts, which has indicated that increased collagen synthesis ac … More companies increased collagen I and III mRNA, were decreased. These results showed that collagen VI expression was regulated independently from that of collagen I and III in fibroblasts. Cutis laxa (CL) is suggested that there are abnormalities in the elastic fiber of connective tissue. We found that increased collagenase activity and collagenase mRNA level were detected in CL fibroblasts. It was suggested that increased collagenase expression of fibroblasts was related to connective tissue abnormality in CL. Finally, collagen metabolism in scleroderma fibroblasts were studied. In localized scleroderma, collagen gene expression in fibroblasts from inflammatory lesions were increased, whereas fibroblasts from sclerotic lesions were unaltered. In systemic sclerosis (SSc), collagen gene expression in cultured fibroblasts were increased in only two of eight strains. On the other hand, collagenase activity and its production were decreased in all SSc fibroblasts. However, no alterations were detected in collagenase mRNA levels. These results suggest that one of mechanisms of collagen deposition in SSc might be caused by decreased collagenase production at the translational or post-translational levels. Less

为了了解结缔组织生理和病理条件下胶原代谢和胶原基因表达的调节，我们研究了组胺、环孢菌素 A、己酮可可碱和肿瘤坏死因子 α (TNF α) 是否影响培养的皮肤成纤维细胞中的胶原合成和胶原降解。 (1-10 微克/毫升) 在翻译前水平刺激胶原蛋白合成，但环孢菌素 A (10^-8>-10^-6M)在降低的治疗浓度下不影响胶原表达α_1(I)胶原和纤连蛋白的mRNA水平在己酮可可碱处理(10-100μg/ml)中。 ) 成纤维细胞抑制胶原蛋白合成以及胶原蛋白 I、III 和纤连蛋白 mRNA 水平，并刺激正常和硬皮病成纤维细胞中胶原酶的表达，而胶原蛋白 VI mRNA 水平则降低。我们还发现，维尔纳综合征成纤维细胞中的 VI 型胶原蛋白表达没有改变，这表明胶原蛋白合成的增加会增加 I 型和 III 型胶原蛋白的 mRNA。这些结果表明，VI 型胶原蛋白的表达独立于 I 型和 III 型胶原蛋白的调节。 III 在成纤维细胞中，皮肤松弛（CL）表明结缔组织弹性纤维存在异常。我们发现在 CL 成纤维细胞中检测到胶原酶活性和胶原酶 mRNA 水平增加。有人认为，CL 中成纤维细胞胶原酶表达增加与结缔组织有关。最后，对硬皮病成纤维细胞中的胶原代谢进行了研究，在局限性硬皮病中，来自炎症病变的成纤维细胞中的胶原基因表达增加，而来自硬化病变的异常成纤维细胞没有改变。在系统性硬化症（SSc）中，培养的成纤维细胞中的胶原蛋白基因表达在八个菌株中只有两个增加。另一方面，所有 SSc 成纤维细胞中胶原酶活性及其产量均下降，但未检测到胶原酶 mRNA 水平发生变化。这些结果表明，SSc 中胶原蛋白沉积的机制之一可能是由翻译或翻译后胶原酶产量减少引起的。翻译水平较低。