Role of Prostaglandin E in Receptor Activator of Nuclear Factor-.KAPPA.B Ligand (RANKL) Expression in Osteoblasts Induced by Cell Adhesion to Bone Marrow B-lymphocytes

Estrogen deficiency caused by ovariectomy (OVX) induces bone loss and increased B-lymphopoiesis in bone marrow. In OVX mice, the production of prostaglandin E (PGE) and the expression of receptor activator of nuclear factor-κB ligand (RANKL) were elevated in osteoblasts, and the cell adhesion of B cells induced RANKL expression in osteoblasts. However, the roles of PGE in RANKL expression and bone resorption are not clear. To examine the relationship between B-lymphopoiesis and PGE production by osteoblasts, B cells were purified from bone marrow, fixed, and co-cultured with mouse osteoblasts. Most of the fixed B cells adhered to cell surface of osteoblasts, and the cell-cell interaction markedly elevated the expression of cyclooxygenase (COX)-2 and membrane-bound PGE synthase (mPGES)-1 mRNAs, and PGE2 production in osteoblasts. Adding B cells also induced the expression of RANKL mRNA in osteoblasts, and the RANKL expression was suppressed by indomethacin, COX-2 inhibitor (NS398) and selective antagonist for PGE receptor EP4, suggesting that PGE production and EP4 signals are involved in RANKL-dependent bone resorption induced by cell-cell contact between B cells and osteoblasts. Therefore, the increased B-lymphopoiesis and PGE production by osteoblasts may contribute to the pathogenesis of osteoporosis due to estrogen deficiency.