Etodolac preserves cartilage-specific phenotype in human chondrocytes: effects on type II collagen synthesis and associated mRNA levels

Abstract

We have shown that interleukin-1 (IL-1) suppresses expression of cartilage-specific types II and IX collagens by cultured human chondrocytes. This inhibition is potentiated by agents which block IL-1-stimulated PGE2 production (J. Clin. Invest. 82:2026, 1988). In contrast, expression of types I and III collagens and fibronectin, matrix components produced by chondrocytes that have lost cartilage-specific phenotype, is increased by IL-1, particularly when IL-1-stimulated synthesis of PGE2 is blocked by a prostaglandin synthetase inhibitor. Etodolac is a new NSAID which is an effective inhibitor of PGE2 synthesis. The enhanced potency of etodolac in chondrocytes (compared with macrophages) suggests that this drug may have selective effects on different target cell types. The present studies were undertaken to compare the effects of etodolac and other nonsteroidal anti-inflammatory drugs (NSAIDs) on IL-1-induced modulation of chondrocyte phenotype. Juvenile human costal chondrocytes or adult articular chondrocytes in primary culture were incubated with etodolac, indomethacin or ketoprofen in the absence or presence of IL-1 beta. After treatment the [3H] proline-labelled collagens were analyzed by SDS-PAGE and type I and type II collagen mRNAs were analyzed by Northern or dot hybridization. Indomethacin (0.3-300 nM) or ketoprofen (2-2000 nM) produced a dose-dependent suppression of type II collagen synthesis associated with decreased levels of type II collagen mRNA in the absence of IL-1, while they potentiated the inhibitory effects of IL-1. In contrast, etodolac (2-2000 nM) maintained expression of type II collagen protein and mRNA. Etodolac unmasked a stimulatory effect of IL-1 on synthesis of type I collagen and fibronectin and levels of type I collagen mRNA, but to a lesser extent than indomethacin. These results suggest that, despite equipotent inhibitory effects of etodolac (IC50 congruent to 10 nM) on PGE2 biosynthesis compared with indomethacin (IC50 congruent to 1.0 nM) or ketoprofen (IC50 congruent to 10 nM), etodolac may be capable of maintaining type II collagen expression by chondrocytes. In vivo this could help to prevent the detrimental effects of mediators such as IL-1 on cartilage matrix synthesis in inflammatory joint diseases.