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.
Jouzeau
J Y
JY
Faculté de Médecine, Laboratoire de Pharmacologie et UMR CNRS UHP 7561, Avenue de la forêt de Haye, Vandoeuvre lès Nancy, 54505, France.
Cipolletta
C
C
Presle
N
N
Netter
P
P
Terlain
B
B
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