Modulation of IL-1 effects on cartilage by NO synthase inhibitors: pharmacological studies in rats.
Objective To compare the ability of L-arginine (L-arg) analog nitric oxide synthase (NOS) inhibitors and isothioureas to restore the interleukin-1 (IL-1) induced inhibition of proteoglycan (PG) synthesis in rat.Methods Chondrocytes beads and patellae were challenged with IL-1betain vitro and monitored for NO production and proteoglycan synthesis. Rats injected with IL-1beta in knee joints were monitored for NO(2)( - )+NO(3)( - )levels in joint tissues and ex-vivo(35)S sulfate incorporation in patellae. NOS inhibitors were either added to culture medium or injected concomittantly to IL-1beta. Results Ability of NOS inhibitors to reduce NO(2)( - )levels decreased from chondrocytes beads to patellae. Partial restoration of PG synthesis was restricted to L-arg analogs in patellae. After IL-1 injection, NO was produced from patella and synovium. L-arg analogs restored partly PG synthesis when decreasing significantly NO(2)( - )+NO(3)( - )levels in synovial fluid. Isothioureas were ineffective. Conclusions NO accounts importantly for IL-1 induced inhibition of cartilage anabolism in rat. L-arg analog NOS inhibitors are more effective than isothioureas in restoring PG synthesis and have chondroprotective potency when administered locally in diseased joint.
Faculté de Médecine, Laboratoire de Pharmacologie et UMR CNRS UHP 7561, Avenue de la forêt de Haye, Vandoeuvre lès Nancy, 54505, France.
J Y
JY
Jouzeau
C
C
Cipolletta
N
N
Presle
P
P
Netter
B
B
Terlain
D000818:Animals; D002356:Cartilage / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009589:Nitrogen Oxides / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013582:Synovial Fluid / Q000378:metabolism
D007375:Interleukin-1; D009589:Nitrogen Oxides; D011509:Proteoglycans; C031701:nitrogen trioxide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase