OBJECTIVE: To determine the effect of antirheumatic drugs and corticosteroids on interleukin-1 receptor (IL-1R) levels in, and IL-1-stimulated metalloprotease synthesis and expression by, normal and osteoarthritic (OA) human articular chondrocytes. METHODS: IL-1R affinity and density of human chondrocytes were determined using radioligand binding experiments. Collagenase and stromelysin synthesis activities were analyzed by 14C-labeled type I collagen and Azocoll assays, respectively. Their messenger RNA (mRNA) levels were determined by Northern blot analysis. IL-1 alpha, IL-1 beta, IL-1 receptor antagonist, and beta 2-microglobulin were measured using enzyme-linked immunosorbent assays. Protein synthesis was determined by 3H-leucine incorporation. RESULTS: Antirheumatic drugs reduced the IL-1R level in normal and OA chondrocytes in a dose-dependent manner. In normal chondrocytes, tenidap reduced the IL-1R level by 44% at 5 micrograms/ml to 88% at 100 micrograms/ml (50% inhibition constant [IC50] 10.1 micrograms/ml), indomethacin reduced IL-1R by 6% at 1.5 micrograms/ml to 43% at 60 micrograms/ml, and naproxen reduced IL-1R by 10% at 10 micrograms/ml to 41% at 300 micrograms/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 indomethacin and naproxen on the IL-1R level was greatly reduced, whereas tenidap still had a marked effect (IC50 22.5 micrograms/ml). Dexamethasone and hydrocortisone had no consistent effect on the IL-1R level. At a therapeutic concentration (20 micrograms/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 stromelysin synthesis and mRNA levels in IL-1-stimulated chondrocytes. CONCLUSION: The suppressive effects of tenidap on IL-1-stimulated metalloprotease synthesis and expression in OA and normal chondrocytes are likely related to a decrease in IL-1R levels. At therapeutic concentrations, 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.
OBJECTIVE: To determine the effect of antirheumatic drugs and corticosteroids on interleukin-1 receptor (IL-1R) levels in, and IL-1-stimulated metalloprotease synthesis and expression by, normal and osteoarthritic (OA) human articular chondrocytes. METHODS:IL-1R affinity and density of human chondrocytes were determined using radioligand binding experiments. Collagenase and stromelysin synthesis activities were analyzed by 14C-labeled type I collagen and Azocoll assays, respectively. Their messenger RNA (mRNA) levels were determined by Northern blot analysis. IL-1 alpha, IL-1 beta, IL-1 receptor antagonist, and beta 2-microglobulin were measured using enzyme-linked immunosorbent assays. Protein synthesis was determined by 3H-leucine incorporation. RESULTS: Antirheumatic drugs reduced the IL-1R level in normal and OA chondrocytes in a dose-dependent manner. In normal chondrocytes, tenidap reduced the IL-1R level by 44% at 5 micrograms/ml to 88% at 100 micrograms/ml (50% inhibition constant [IC50] 10.1 micrograms/ml), indomethacin reduced IL-1R by 6% at 1.5 micrograms/ml to 43% at 60 micrograms/ml, and naproxen reduced IL-1R by 10% at 10 micrograms/ml to 41% at 300 micrograms/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 indomethacin and naproxen on the IL-1R level was greatly reduced, whereas tenidap still had a marked effect (IC50 22.5 micrograms/ml). Dexamethasone and hydrocortisone had no consistent effect on the IL-1R level. At a therapeutic concentration (20 micrograms/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 stromelysin synthesis and mRNA levels in IL-1-stimulated chondrocytes. CONCLUSION: The suppressive effects of tenidap on IL-1-stimulated metalloprotease synthesis and expression in OA and normal chondrocytes are likely related to a decrease in IL-1R levels. At therapeutic concentrations, 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.
Authors: P F Moore; D L Larson; I G Otterness; A Weissman; S B Kadin; F J Sweeney; J D Eskra; A Nagahisa; M Sakakibara; T J Carty Journal: Inflamm Res Date: 1996-02 Impact factor: 4.575
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