The mechanism of inhibition of endothelin-1-induced stimulation of DNA synthesis in rat articular chondrocytes.
Endothelin-1 (ET-1) is a potent mitogen for rat articular chondrocytes (AC) in short term culture (24 h). Prolonged incubation (72 h) of AC with ET-1 resulted in inhibition of [3H]thymidine incorporation. This inhibition seemed to be mediated by prostaglandins (PGs) released in response to ET-1, since indomethacin (INDO) enhanced ET-1-induced [3H]thymidine incorporation. In agreement with this hypothesis, exogenous prostaglandins (PGE2, PGF2alpha and TxB2) blocked all basal, ET-1-induced and ET-1 induced-INDO-enhanced [3H]thymidine incorporation and ET-1 stimulated PGE2 release in a time and concentration-dependent manner. INDO also blocked cGMP production and 6-anilino-5,8-quinolinedione, a relatively specific inhibitor of cGMP formation, enhanced the stimulation and suppressed the inhibition of ET-1-induced DNA synthesis. In addition, 8-bromo-cGMP, an analogue of cGMP, blocked at all time periods studied, both basal and ET-1-induced incorporations of [3H]thymidine. Thus, PGs produced in response to ET-1 counteract the ET-1-induced stimulation of [3H]thymidine incorporation into rat AC by increasing cGMP production.
Khatib
A M
AM
INSERM Unit 349, Biologie Cellulaire et Moleculaire de l'Os et du Cartilage, Hôpital Lariboisiere, Paris, France.
Ribault
D
D
Quintero
M
M
Barbara
A
A
Fiet
J
J
Mitrovic
D R
DR
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects*; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006157:Guanosine Monophosphate / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013936:Thymidine; D014316:Tritium
D000634:Aminoquinolines; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D014316:Tritium; D006157:Guanosine Monophosphate; C041715:6-anilino-5,8-quinolinedione; D013936:Thymidine