REGULATION OF HUMAN NORMAL AND OSTEOARTHRITIC CHONDROCYTE INTERLEUKIN-1 RECEPTOR BY ANTIRHEUMATIC DRUGS

Objective. To determine the effect of antirheumatic drugs and corticos teroids on interleukin-1 receptor (IL-1R) levels in, and IL-1-stimulat ed metalloprotease synthesis and expression by, normal and osteoarthri tic (OA) human articular chondrocytes. Methods. IL-1R affinity and den sity of human chondrocytes were determined using radioligand binding e xperiments. Collagenase and stromelysin synthesis activities were anal yzed by C-14-labeled type I collagen and Azocoll assays, respectively. Their messenger RNA (mRNA) levels were determined by Northern blot an alysis. IL-1alpha, IL-1beta, IL-1 receptor antagonist, and beta2-micro globulin were measured using enzyme-linked immunosorbent assays. Prote in synthesis was determined by H-3-leucine incorporation. Results. Ant irheumatic drugs reduced the IL-1R level in normal and OA chondrocytes in a dose-dependent manner. In normal chondrocytes, tenidap reduced t he IL-1R level by 44% at 5 mug/ml to 88% at 100 mug/ml (50% inhibition constant [IC50] 10.1 mug/ml), indomethacin reduced IL-1R by 6% at 1.5 mug/ml to 43% at 60 mug/ml, and naproxen reduced IL-1R by 10% at 10 m ug/ml to 41% at 300 mug/ml; the effects observed with indomethacin and naproxen occurred only when the drugs were used at levels above their therapeutic concentrations. In OA chondrocytes, the effect of indomet hacin and naproxen on the IL-1R level was greatly reduced, whereas ten idap still had a marked effect (IC50 22.5 mug/ml). Dexamethasone and h ydrocortisone had no consistent effect on the IL-1R level. At a therap eutic concentration (20 mug/ml), tenidap was found to reduce the IL-1R level in a time-dependent manner, with maximum inhibition (98%) by 48 hours. Tenidap was also found to markedly reduce collagenase and stro melysin synthesis and mRNA levels in IL-1-stimulated chondrocytes. Con clusion. The suppressive effects of tenidap on IL-1-stimulated metallo protease synthesis and expression in OA and normal chondrocytes are li kely related to a decrease in IL-1R levels. At therapeutic concentrati ons, tenidap has a greater effect on the IL-1R level than is seen with indomethacin or naproxen, and glucocorticoids have no effect on IL-1R .