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

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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