Prostaglandin receptor Ep2 mediates PGE2 stimulated hypercalcemia in mice in vivo

Prostaglandin E-2 (PGE(2)) can stimulate bone resorption by a cyclic AMP-dependent pathway. Two PGE(2) receptors, EP2 and EP4, have been shown to play a role in PGE(2) stimulation of osteoclast formation. In primary osteoblastic cell cultures from EP2 wild type (EP2 +/+) mice, PGE(2) (0.1 muM) increased cyclic AMP production 3.5-fold, but PGE(2) had no effect on cells from mice in which the EP2 receptor had been deleted (EP2 -/-). To examine the role of the EP2 receptor in the resorption response in vivo we injected PGE(2) in EP2 -/- mice, and compared them with EP2 +/+ mice. Injection of PGE(2) (3 mg/kg, four times daily for three days) in 9- to 12-month-old male mice on a 129 SvEv background increased serum calcium from 9.8 +/- 0.5 to 10.7 +/- 0.3 mg/dl (P < 0.01) in EP2 +/+ mice but not in EP2 -/- mice (10.1 +/- 0.3 vs. 10.2 +/- 0.3 mg/dl). PGE(2) injection (6 mg/kg twice a day for three days) in 3-4 month old male mice on a C57 BL/6 x 129 SvEv background increased calcium from 8.2 +/- 0.1 to 9.0 +/- 0.3 mg/dl (P < 0.05) in EP2 +/+ mice but had no effect in EP2 mice (8.4 +/- 0.1 vs. 8.3 +/- 0.2 mg/dl). Injection of PGE(2) over the calvariae of EP2 +/+ and EP2 mice increased the expression of receptor activator of nuclear factor kappaB ligand (RANYL) both locally and in the tibia, but RANYL responses were lower in EP2 -/- mice. We conclude that EP2 receptor plays a role in the hypercalcemic response to PGE(2). This impaired response in EP2 -/- mice may be due to decreased ability to stimulate cyclic AMP and in part, to a smaller increase in the expression of RANKL m-RNA. (C) 2002 Elsevier Science Inc. All rights reserved.