Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis.
OBJECTIVE
To study the mechanisms responsible for the cross-talk between lipoxygenase (LOX) and cyclooxygenase (COX) pathways in human osteoarthritic (OA) synovial explants, and to confirm the arachidonic acid (AA) shunting phenomenon and its influence on interleukin 1beta (IL-1beta) synthesis.


METHODS
Synovial membrane explants were cultured in the absence or presence of different drugs that inhibit COX and/or LOX activities. Concentrations of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), lipoxin A4 (LXA4), and IL-1beta were measured.


RESULTS
When membrane explants were incubated with naproxen (COX inhibitor) under unstimulated conditions, the production of LTB4 was dose-dependently enhanced, reaching a 5-fold increase over the control. This shunt could be partially reversed by the addition of exogenous PGE2. Under lipopolysaccharide (LPS) stimulation, both licofelone (COX/LOX inhibitor) at therapeutic concentrations and NDGA (LOX inhibitor) inhibited LTB4 production, whereas naproxen did not amplify the LPS-induced LTB4 production. Conversely, using NDGA, it was found that a shunt of AA from the LOX to the COX pathway did not occur. Under LPS conditions, both naproxen and licofelone inhibited LXA4, inducing an increase in the LTB4/LXA4 ratio with naproxen treatment but not with licofelone. Under these conditions, naproxen treatment induced a higher level of IL-1beta production.


CONCLUSIONS
We demonstrated in OA synovium that a shunt from AA to the LOX pathway occurred and that treatment with a nonselective COX inhibitor could increase the production of LTB4 and secondarily the synthesis of IL-1beta. Therefore treatment with licofelone, which can act on both COX and LOX pathways, may have some interesting properties in the treatment of OA.
Marcouiller
Patrick
P
Osteoarthritis Research Unit, Hôpital Notre-Dame, Centre hospitalier de l'Université de Montréal, Montréal, Québec.
Pelletier
Jean-Pierre
JP
Guévremont
Mélanie
M
Martel-Pelletier
Johanne
J
Ranger
Pierre
P
Laufer
Stefan
S
Reboul
Pascal
P
D000085:Acetates / Q000494:pharmacology; D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology; D020370:Osteoarthritis, Knee / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D000085:Acetates; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D008070:Lipopolysaccharides; D011758:Pyrroles; D007975:Leukotriene B4; D016718:Arachidonic Acid; D009288:Naproxen; D009637:Masoprocol; D015232:Dinoprostone; C088092:licofelone