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

为了了解结缔组织在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、环孢素A、己酮可可碱和肿瘤坏死因子α对培养的皮肤成纤维细胞胶原合成和胶原降解的影响。组胺(1-10µg/ml)刺激翻译前水平的胶原合成，而环孢素A(10^&lt；-8&gt；-10^&lt；-6&gt；M)在治疗浓度下不影响胶原的表达。己酮可可碱(10-100µg/ml)可降低成纤维细胞α_1(I)胶原和纤维连接蛋白的mRNA水平。肿瘤坏死因子抑制正常和硬皮病成纤维细胞的胶原合成和I、III型胶原及纤维连接蛋白的mRNA水平，并刺激胶原酶的表达，而VI型胶原的mRNA水平无明显变化。我们还发现在沃纳综合征成纤维细胞中有VI型胶原的表达，这表明…增加了胶原的合成更多的公司增加了I型胶原和III型胶原的mRNA，分别减少了。这些结果表明，在成纤维细胞中，VI型胶原的表达独立于I型和III型胶原的表达。皮肤松弛(CL)提示结缔组织的弹性纤维存在异常。我们发现，在CL成纤维细胞中，胶原酶活性和胶原酶mRNA水平均升高。提示成纤维细胞胶原酶表达增加与结缔组织异常有关。最后，对硬皮病成纤维细胞的胶原代谢进行了研究。在局限性硬皮病中，炎性病变成纤维细胞的胶原基因表达增加，而硬化性病变成纤维细胞的胶原基因表达无变化。在系统性硬化症(SSC)中，仅有2株培养的成纤维细胞胶原基因表达增加。另一方面，所有SSC成纤维细胞的胶原酶活性及其产量均降低。然而，胶原酶基因表达水平并未检测到变化。这些结果表明，SSC中胶原沉积的机制之一可能是翻译或翻译后胶原酶产生减少所致。较少

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