Constitutive expression of a 92-kD gelatinase (type V collagenase) by rheumatoid synovial fibroblasts and its induction in normal human fibroblasts by inflammatory cytokines

• Published in: The Journal of clinical investigation Vol. 88; no. 5; pp. 1656 - 1662
• Main Authors: UNEMORI, E. N, HIBBS, M. S, AMENTO, E. P
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 01.11.1991
• Subjects: Arthritis, Rheumatoid - enzymology; Biological and medical sciences; Cells, Cultured; Cytokines - pharmacology; Diseases of the osteoarticular system; Fibroblasts - enzymology; Gelatinases; Humans; Interleukin-1 - pharmacology; Lymphotoxin-alpha - pharmacology; Medical sciences; Pepsin A - biosynthesis; Synovial Membrane - enzymology; Tumor Necrosis Factor-alpha - pharmacology; Human; Pathology; Pathophysiology; Inflammatory arthritis; Diseases of the osteoarticular system; Cytokine; Exploration; Inflammatory joint disease; Experimental study; Fibroblast
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci115480

Synovial fibroblasts freshly isolated from the rheumatoid joint are characterized by their marked connective tissue degradative ability. This phenotype includes the ability to secrete large amounts of the matrix-degrading metalloproteinases, collagenase, and stromelysin. We have found that another aspect of this phenotype is the constitutive expression at both protein and mRNA levels of a 92-kD gelatinolytic metalloproteinase, which is not secreted by normal dermal or lung fibroblasts and is immunologically cross-reactive with a type V collagenase expressed by activated macrophages and neutrophils. Expression of this 92-kD metalloproteinase confers upon the fibroblasts the capacity to degrade collagenase- and stromelysin-resistant interstitial elements, such as collagen types IV, V and XI. In contrast to the 92-kD metalloproteinase, a 68-kD gelatinase (type IV collagenase) was expressed by all fibroblast types studied, indicating that its regulation is distinct from that of the 92-kD gelatinase. To identify what cytokines may be important in the induction of the rheumatoid synovial phenotype, including expression of the 92-kD gelatinase, we exposed normal dermal fibroblasts to a number of cytokines including many known or considered likely to be present in rheumatoid synovial fluid and tissue. Although IL-1 beta, tumor necrosis factor-alpha, lymphotoxin, platelet-derived growth factor, and basic fibroblast growth factor were capable of stimulating fibroblasts to secrete collagenase, only tumor necrosis factor-alpha, lymphotoxin, and IL-1 beta were able to induce expression of the 92-kD gelatinase, demonstrating discordant regulation of the two metalloproteinases. Expression of the 68-kD gelatinase was independent of that of the 92-kD gelatinase, as demonstrated at the protein and mRNA levels. Late passage rheumatoid synovial fibroblasts, which no longer constitutively expressed the 92-kD gelatinase, displayed an accentuated response to IL-1 beta when compared to normal dermal fibroblasts. Thus, in addition to IL-1 beta, tumor necrosis factor-alpha or lymphotoxin may contribute to the expression of a specific rheumatoid synovial phenotype in vivo that is associated with progressive matrix destruction.