Modulation of glucocorticoid receptor expression in human articular chondrocytes by cAMP and prostaglandins.
Endogenous glucocorticoids are believed to be extremely important in the maintenance of cellular homeostasis through their binding to specific cell receptors. In normal articular cartilage, physiological concentrations of cortisol are potentially capable of suppressing metalloprotease synthesis by chondrocytes. This hormone action is likely to represent one of the major pathways through which the catabolism of cartilage under normal physiological conditions is kept in a homeostatic state. In osteoarthritis (OA), a severe reduction in the glucocorticoid receptor (GR) level in chondrocytes is evident and could produce cellular steroid resistance in terms of the synthesis of destructive enzymes. Our aim was to look at agents which could upregulate GR expression in human chondrocytes. In this context, we have analyzed the effect of prostaglandins of the E series and cyclic AMP on normal and OA human articular chondrocytes. Dibutyryl cAMP at a concentration of 25 micrograms/ml, as well as prostaglandin E2 (PGE2) at 1 microgram/ml, increased the GR level. Although the GR level is dramatically reduced in OA chondrocytes, the sensitivity of the latter cells to both cAMP and PGE2 is similar. Synthetic PGE1 at therapeutic concentrations also induced identical upregulation of GR expression in chondrocytes. The addition of synthetic prostaglandins to the antiinflammatory glucocorticoid dosage regimen may prove to be of major therapeutic importance in the treatment of arthritic diseases by potentiating the effects of glucocorticoid on the reduction of the catabolism of articular cartilage.
DiBattista
J A
JA
Rheumatic Disease Unit Research Laboratory, Notre-Dame Hospital Research Center, Montreal, PQ, Canada.
Martel-Pelletier
J
J
Cloutier
J M
JM
Pelletier
J P
JP
D000527:Alprostadil / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D011453:Prostaglandins / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D011453:Prostaglandins; D011965:Receptors, Glucocorticoid; D000242:Cyclic AMP; D000527:Alprostadil; D015232:Dinoprostone