Endothelin-1 induces loss of proteoglycans and enhances fibronectin and collagen production in cultured rabbit synovial cells.
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 microgram hydroxyproline/microgram DNA in basal, P < 0.05) and fibronectin protein synthesis (157 +/- 14% of [35S] methionine incorporation vs. basal, P < 0.05). The endothelin ETA 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 ETA receptors.
Gutierrez
S
S
Inflammation Unit, Fundación Jiménez Díaz, UAM, Madrid, Spain.
Palacios
I
I
Egido
J
J
Gómez-Garre
D
D
Hernández
P
P
González
E
E
Herrero-Beaumont
G
G
D000818:Animals; D003094:Collagen / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D011817:Rabbits; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D005353:Fibronectins; D006025:Glycosaminoglycans; D010456:Peptides, Cyclic; D011509:Proteoglycans; D003094:Collagen; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D007213:Indomethacin