TUMOR-NECROSIS-FACTOR-ALPHA AND EPIDERMAL GROWTH-FACTOR REGULATION OF COLLAGENASE AND STROMELYSIN IN ADULT PORCINE ARTICULAR CHONDROCYTES

Chondrocyte-derived metalloproteases have been postulated to play a role in the degradation of articular cartilage during the development of chronic arthritic disorders. TNF-alpha (tumor necrosis factor alpha), an inflammatory mediator released by activated macrophages, has been detected in the synovial fluid of patients with rheumatoid diseases. We have found that TNF-alpha is a potent stimulator of collagenase and stromelysin mRNA accumulation, collagenase activity, and immunoprecipitable stromelysin in monolayer cultures of adult porcine articular chondrocytes. In contrast EGF (epidermal growth factor), which stimulates collagenase and/or stromelysin synthesis in fibroblast systems, stimulated minimal amounts of these enzymes at both the message and protein levels. Nuclear run-on transcription analysis demonstrated that the TNF-alpha-stimulated increase in stromelysin and collagenase message levels was, at least partially, due to increased transcription. Elevated transcription of these genes, in response to TNF-alpha, was apparent by at least 2 hours post-stimulation. The degree of c-fos and c-jun stimulation by TNF-alpha or EGF did not correlate with the levels of collagenase and stromelysin message stimulated by these factors. EGF stimulated significant accumulation of both c-fos and c-jun mRNAs while only very low amounts of these messages were stimulated by TNF-alpha. Our data suggests that TNF-alpha may contribute to articular cartilage degradation by stimulating chondrocyte-derived matrix metalloprotease. In addition the regulation of metalloprotease genes in chondrocytes may be different from their regulation in fibroblasts.