DIFFERENTIAL-EFFECTS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON CONSTITUTIVE AND INDUCIBLE PROSTAGLANDIN G H SYNTHASE IN CULTURED BONE-CELLS/

The production of prostaglandins by osteoblasts is an important mechan ism for the regulation of bone turnover, Bone cells contain both induc ible and constitutive prostaglandin G/H synthase (PGHS-2 and PGHS-1) a nd these are differentially regulated, Nonsteroidal anti-inflammatory drugs (NSAIDs), which selectively inhibit one of these enzymes, would be useful in assessing their relative roles in bone metabolism, By Nor thern analysis, only PGHS-2 is expressed by the immortalized rat osteo blastic cell line, Py1a, while only PGHS-1 is expressed by the rat ost eosarcoma cell line, ROS 17/2.8. We tested the relative inhibitory pot ency (IC50) of seven different NSAIDs on these two cell lines, A recen tly described selective inhibitor of PGHS-2 NS-398, was approximately 30 times more potent in inhibiting PGHS-2 than PGHS-1, and diclofenac was approximately 10 times more potent, Both had IC50's of approximate ly 3 nM for PGHS-2 in Py1a cells, Indomethacin, flurbiprofen, naproxen , and piroxicam were relatively nonselective,vith IC50's ranging from 30 nM to 1 mu M, while 6-methoxy-2 naphthyl acetic acid, the active me tabolite of nabumetone, was inhibitory only at concentrations greater than 1 mu M. These results indicate that the presently available NSAID s are unlikely to distinguish completely between effects mediated by P GHS-2 or PGHS-1. However, the cell systems employed could provide a mo del for the analysis of new compounds with greater selective activity.