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OBJECTIVE: Prostaglandins are important mediators in bone metabolism and in pathologies such as rheumatoid arthritis and osteoarthritis. We investigated the roles of cyclooxygenases (COX) and prostaglandin receptors in the accumulation of osteoprotegerin (OPG) in the supernatants of human osteoblasts in culture. METHODS: Three different cellular models were used, the human osteosarcoma cell lines MG-63 and Saos-2, and primary cultures of human osteoblasts. OPG concentrations were determined by ELISA. RESULTS: RT-PCR analysis showed that, like primary human osteoblasts, MG-63 cells express DP, EP4, FP, IP, and TP receptors, whereas the Saos-2 cells lack IP. Concentration of OPG was highest in MG-63 cell supernatants (36 +/- 12.5 ng/ml), followed by human osteoblasts (12.77 +/- 2.2 ng/ml) and Saos-2 (3.6 +/- 0.76 ng/ml). COX inhibitors did not alter these values. Prostaglandin E2 and BW 245C (a synthetic DP receptor agonist) decreased OPG in the supernatants of human osteoblasts but not in immortalized cell lines. These effects were concentration-dependent and were inhibited by EP4 and DP receptor antagonists. Fluprostenol, an FP receptor agonist, increased the accumulation of OPG in MG-63 but not in primary human osteoblasts or Saos-2. CONCLUSION: Our results show that activation of EP4 or DP receptors decreased the accumulation of OPG in supernatants of osteoblasts in culture, and suggest that these receptors could be interesting pharmacological targets in bone diseases. They also demonstrate important differences between primary osteoblasts and immortalized cell lines, both in the distribution and in the effects mediated by prostaglandin receptors.