Effects of bisphosphonates on prostaglandin E2 and thromboxane B2 production in human whole blood and monocytes stimulated by lipopolysaccharide and A23187

Bisphosphonates are antiatherosclerotic, suppress monocyte-macrophages, and modulate proinflammatory mediators. Prostaglandin (PG) E 2 , thromboxane (TX) A 2 , and cyclooxygenase-2 (COX-2) enzyme are involved in inflammation and atherosclerosis. We studied the effects of four bisphosphonates (etidronate, clodronate, tiludronate, and alendronate) on PGE 2 and TXB 2 production in human whole blood and monocyles. PGE 2 and TXB 2 were determined by direct radioimmunoassay and COX-2 expression by Western blot. In whole blood, the bisphosphonates did not modulate the increase in PGE 2 and TXB 2 concentrations induced by calcium ionophore A23187 or lipopolysaccharide (LPS). None of the bisphosphonates did change PGE 2 and TXB 2 concentration after spontaneous clotting. A23187- and spontaneous clotting-induced PGE 2 and TXB 2 productions were inhibited over 90% hy acetylsalicylic acid (ASA), and LPS-induced PGE 2 and TXB 2 formations were inhibited over 90% hy nimesulide. None of the bisphosphonates altered these inhibitions. In monocyles, etidronate and clodronate augmented A23187-stimulated PGE 2 production 2.5- to 3.2-fold (p < 0.05). LPS- or A2318-induced elevations in TXB 2 were not influenced hy the bisphosphonates. The tested bisphosphonates neither induced COX-2 expression nor modulated LPS-induced COX-2 expression in monocytes. The results suggest that the antiatherosclerotic effects of hisphosphonates are not mediated via PGE 2 , TXA 2 , or COX-2, and the bisphosphonates do not interfere with the suppression of platelet COX-1 activity by ASA and COX-2 activity by nimesulide.