Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / metabolism
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Adenylyl Cyclases / metabolism
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Animals
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Blotting, Northern
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Bone and Bones / cytology
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Bone and Bones / drug effects
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Bone and Bones / metabolism
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Calcium / blood
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cyclic AMP / biosynthesis
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Dinoprostone / blood
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Dinoprostone / metabolism
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Dinoprostone / pharmacology*
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
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Glycoproteins / metabolism
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Hypercalcemia / blood
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Hypercalcemia / chemically induced
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Hypercalcemia / metabolism*
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Osteoblasts / drug effects
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Osteoblasts / enzymology
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Osteoblasts / metabolism
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Osteoclasts / cytology
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Osteoclasts / drug effects
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Osteoclasts / metabolism
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Osteogenesis / drug effects
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Osteoprotegerin
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RANK Ligand
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Prostaglandin E / genetics
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Receptors, Prostaglandin E / metabolism
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Receptors, Prostaglandin E / physiology*
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Tumor Necrosis Factor
Substances
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Actins
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Carrier Proteins
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Glycoproteins
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Membrane Glycoproteins
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Osteoprotegerin
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Ptger2 protein, mouse
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RANK Ligand
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RNA, Messenger
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Tumor Necrosis Factor
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Cyclic AMP
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
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Adenylyl Cyclases
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Dinoprostone
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Calcium