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

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、戊茶碱和肿瘤坏死因子α（TNF α）是否影响培养的皮肤成纤维细胞中胶原合成和胶原降解。组胺（1-10 μ g/ml）在翻译前水平刺激胶原合成，而环孢素A（10 μ <-8>M-10 μ <-6>M）在治疗浓度下不影响胶原表达。在戊氨酰茶碱处理（10-100 μ g/ml）的成纤维细胞中，α_1（I）胶原和纤连蛋白的mRNA水平降低。TNF抑制胶原合成和胶原I，III，和纤连蛋白的mRNA水平，并刺激胶原酶在正常和硬皮病成纤维细胞的表达，而胶原VI的mRNA水平不变。我们还发现，胶原VI在沃纳综合征成纤维细胞中的表达，这表明胶原合成的增加是导致纤维化的重要因素。 关于我们 I型胶原和III型胶原mRNA表达增加，而I型胶原和III型胶原mRNA表达减少。这些结果表明，VI型胶原蛋白的表达调节独立于胶原蛋白I和III在成纤维细胞。皮肤松弛拉克萨（CL）提示结缔组织弹性纤维异常。我们发现，增加胶原酶活性和胶原酶mRNA水平检测CL成纤维细胞。提示成纤维细胞胶原酶表达增加与CL结缔组织异常有关。最后，研究了硬皮病成纤维细胞的胶原代谢。在局限性硬皮病中，炎性病变的成纤维细胞胶原基因表达增加，而硬皮病病变的成纤维细胞不变。在系统性硬化症（SSc），胶原蛋白基因表达在培养的成纤维细胞增加，只有两个8株。另一方面，胶原酶活性和其生产在所有SSc成纤维细胞减少。然而，胶原酶mRNA水平未检测到变化。这些结果提示，SSc中胶原沉积的机制之一可能是翻译或翻译后水平胶原酶产生减少所致。少

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