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 (I L-1) induced inhibition of proteoglycan (PG) synthesis in rat. Methods: Chondrocytes beads and patellae were challenged with IL-1 beta in vitro and monitored for NO production and proteoglycan synthesis. Rats inje cted with IL-1 beta in knee joints were monitored for NO2- + NO3- levels in joint tissues and ex-vivo S-35 sulfate incorporation in patellae. NOS inhi bitors were either added to culture medium or injected concomittantly to IL -1 beta. Results: Ability of NOS inhibitors to reduce NO2- levels decreased from cho ndrocytes beads to patellae. Partial restoration of PG synthesis was restri cted to L-arg analogs in patellae. After IL-1 injection, NO was produced fr om patella and synovium. L-arg analogs restored partly PG synthesis when de creasing significantly NO2- + NO3- levels in synovial fluid. Isothioureas w ere ineffective. Conclusions: NO accounts importantly for IL-1 induced inhibition of cartila ge anabolism In rat. L-arg analog NOS inhibitors are more effective than is othioureas in restoring PG synthesis and have chondroprotective potency whe n administered locally in diseased joint.