EFFECTS OF STEROID, NONSTEROIDAL ANTI-INFLAMMATORY DRUGS, AND COX-2 SELECTIVE INHIBITORS ON PROLIFERATION AND CYTOTOXICITY IN HUMAN OSTEOBLASTS

Abstract

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to suppress bone repair and remodeling in vivo. Our previous studies showed that NSAIDs inhibited osteoblast proliferation and induced cell death in fetal rat osteoblast cultures. However, the NSAIDs effects on the functions of human osteoblasts remain unclear. Newly developed selective cyclo-oxygenase 2 (COX-2) inhibitors, celecoxib and refecoxib, have been reported to have lower risk of gastrointestinal complications than traditional nonsteroidal anti-inflammatory drugs. A recent report showed that refecoxib decreased bone ingrowth in an animal study. However, the effects of COX-2 selective inhibitors on human osteoblasts have rarely been investigated. In this study, the effects of steroid, non-selective, and selective COX-2 inhibitors on proliferation, cell cycle kinetics, and cytotoxicity in cultured human osteoblasts were examined.

Materials and Methods: Indomethacin,ketorolac,piroxicam, and diclofenac (10⁻⁵ and 10⁻⁴M); dexamethasone (10⁻⁷ and 10⁻⁶M); Celecoxib and DFU, an analogue of rofecoxib, (10⁻⁷–10⁻⁴M) were tested for 24 or 48 hr in human osteoblast cultures.

Results: In this study, we found that a 24 hour treatment of COX-2 selective inhibitors, celecoxib and DFU, significantly inhibited proliferation, arrested cell cycle, and had cytotoxicity in cultured human osteoblasts. However, the inhibitory effect on proliferation could be reversed if these agents were withdrawn for 24 hours. Indomethacin, ketorolac, diclofenac, and piroxicam also significantly inhibited proliferation and arrested cell cycle at the G₀/G₁ phase, but had no cytotoxic effects on human osteoblasts.

Discussion: These results suggest that the COX-2 selective and non-selective NSAIDs may affect osteoblastic functions through different mechanisms.