Differential regulation of PAI-1 gene expression in human fibroblasts predisposed to a fibrotic phenotype

Synthesis of the major negative physiologic regulator of plasmin activation [plasminogen activator inhibitor type-1 (PAI-1)] is elevated during progre ssive cellular senescence, in premature aging disorders (e.g., Werner's syn drome), and in conditions associated with tissue fibrosis and excessive fib rin accumulation (e.g., sclerosis, keloid formation). Dermal fibroblasts de rived from Werner's patients as well as from keloid lesions markedly overex press PAI-1 mRNA transcripts compared to normal skin fibroblasts. Such cell type-related differences in steady-state PAI-1 mRNA content, and variances in the relative abundance of the 3.0- compared to the 2.2-kb PAI-1 mRNA sp ecies, served to discriminate normal from Werner's and keloid fibroblasts. This disparity in PAI-1 mRNA levels paralleled transcriptional activities o f the PAI-1 gene; de no;o synthesis of PAI-1 protein among the three cell t ypes, moreover, closely approximated the respective differences in total PA I-1 mRNA content. Despite the markedly elevated levels of PAI-1 mRNA and pr otein evident in newly confluent keloid fibroblasts, these cells effectivel y suppressed PAI-1 synthesis (as did normal dermal fibroblasts) upon cultur e in serum-free medium. Werner's syndrome skin fibroblasts, in contrast, co ntinued to maintain high-level PAI-1 expression even after 3 days of growth arrest. Adhesion-mediated attenuation of serum-stimulated PAI-1 expression , a characteristic of normal cells involving sequences which mapped to the distal 5' flanking region of the PAI-1 gene, was retained in keloid but not Werner's fibroblasts. Collectively, these data suggest that (1) specific c ontrols on PAI-1 gene expression are fundamentally different between these two clinically significant high PAI-1-synthesizing cell types and (2) the l ocalized keloid may define the emergence of a distinct profibrotic dermal f ibroblastoid phenotype in genetically predisposed individuals. (C) 1991 Aca demic Press.