Endothelin-1 induces loss of proteoglycans and enhances fibronectin and collagen production in cultured rabbit synovial cells

Abstract

Endothelin-1 exerts a wide range of biological actions besides its characteristic vasoconstrictor function. The potential participation of endothelin-1 in rheumatic diseases has hardly been explored. We have studied the possible role of endothelin-1 as a modulator of extracellular matrix turnover in cultured rabbit synoviocytes. In relation to basal levels, endothelin-1 increased the mRNA levels of collagen I and fibronectin at 24 h (130 ± 9% and 132 ± 18%, respectively), but did not modify the expression of decorin core proteoglycan. Endothelin-1 also decreased proteoglycan metabolism (about 50% of proteoglycan synthesis inhibition and 270 ± 32% of degradation rate vs. basal, P < 0.05 in both cases) and enhanced total collagen (1.5 ± 0.5 vs. 0.8 ± 0.2 μg hydroxyproline/μg DNA in basal, P < 0.05) and fibronectin protein synthesis (157 ± 14% of [ 35S]methionine incorporation vs. basal, P < 0.05). The endothelin ET A receptor antagonist BQ-123 (Cyclo d-trp- d-asp-pro- d-val-leu) displaced [ 125I]endothelin-1 binding and inhibited endothelin-1 effects on extracellular matrix components. The cell incubation with indomethacin totally reversed the endothelin-1 effect. These data suggest that endothelin-1 may be an important mediator of the pathogenesis of joint damage, disturbing the extracellular synovial matrix turnover through the endothelin ET A receptors.