Prostaglandin receptor EP2 mediates PGE2 stimulated hypercalcemia in mice in vivo.

Li X, Tomita M, Pilbeam CC, Breyer RM, Raisz LG
Prostaglandins Other Lipid Mediat. 2002 67 (3-4): 173-80

PMID: 12013525 · DOI:10.1016/s0090-6980(01)00186-1

Prostaglandin E2 (PGE2) can stimulate bone resorption by a cyclic AMP-dependent pathway. Two PGE2 receptors, EP2 and EP4 have been shown to play a role in PGE2 stimulation of osteoclast formation. In primary osteoblastic cell cultures from EP2 wild type (EP2 +/+) mice, PGE2 (0.1 microM) increased cyclic AMP production 3.5-fold, but PGE2 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 PGE2 in EP2 -/- mice, and compared them with EP2 +/+ mice. Injection of PGE2 (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). PGE2 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 PGE2 over the calvariae of EP2 +/+ and EP2-/- mice increased the expression of receptor activator of nuclear factor kappaB ligand (RANKL) both locally and in the tibia, but RANKL responses were lower in EP2 -/- mice. We conclude that EP2 receptor plays a role in the hypercalcemic response to PGE2. 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 mRNA.

MeSH Terms (28)

Actins Adenylyl Cyclases Animals Blotting, Northern Bone and Bones Calcium Carrier Proteins Cyclic AMP Dinoprostone Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) Glycoproteins Hypercalcemia Male Membrane Glycoproteins Mice Mice, Inbred C57BL Mice, Knockout Osteoblasts Osteoclasts Osteogenesis Osteoprotegerin RANK Ligand Receptor Activator of Nuclear Factor-kappa B Receptors, Cytoplasmic and Nuclear Receptors, Prostaglandin E Receptors, Prostaglandin E, EP2 Subtype Receptors, Tumor Necrosis Factor RNA, Messenger

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