Endogenous glucocorticoids are of prime importance in the maintenance of cellular homeostasis through their binding to specific cell receptors. Under normal conditions, physiological concentrations of cortisol are potentially capable of suppressing metalloprotease synthesis by chondrocytes and synoviocytes. This hormone action is like to represent one of the major pathways through which the catabolism of cartilage under physiological conditions is kept in a homeostatic state. In osteoarthritis (OA), a severe reduction (about 50%) in the glucocorticoid receptor (GR) level in chondrocytes was found to be sufficient to alter the cellular steroid resistance in terms of the synthesis of destructive enzymes. Prostaglandins of the E series and dibutyryl cyclic AMP increased the GR level in normal and OA human articular chondrocytes. Synthetic PGE(1) (misoprostol) also induced upregulation of GR expression in chondrocytes. Naproxen and indomethacin, but not tiaprofenic acid, at therapeutic concentrations, significantly reduced the level of GR in synovial cells. This effect could be reversed by the additionl of misoprostol. These findings bring insight into the differential effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the GR system and may provide an explanation for the reduced level of GR found in OA chondrocytes. The addition of synthetic prostaglandins may prove to be of therapeutic importance in the treatment of arthritic diseases by potentiating the effects of therapeutically administered glucocorticoid on the reducation of the catabolism of articular cartilage.