Abstract
Prostaglandin (PG) E2 is a potent inducer of cortical and trabecular bone formation in humans and animals. Although the bone anabolic action of PGE2 is well documented, the cellular and molecular mechanisms that mediate this effect remain unclear. This study was undertaken to examine the effect of pharmacological inactivation of the prostanoid receptor EP4, one of the PGE2 receptors, on PGE2-induced bone formation in vivo. We first determined the ability of EP4A, an EP4-selective ligand, to act as an antagonist. PGE2 increases intracellular cAMP and suppresses apoptosis in the RP-1 periosteal cell line. Both effects were reversed by EP4A, suggesting that EP4A acts as an EP4 antagonist in the cells at concentrations consistent with its in vitro binding to EP4. We then examined the effect of EP4 on bone formation induced by PGE2in young rats. Five- to 6-week-old rats were treated with PGE2 (6 mg/kg/day) in the presence or absence of EP4A (10 mg/kg/day) for 12 days. We found that treatment with EP4A suppresses the increase in trabecular bone volume induced by PGE2. This effect is accompanied by a suppression of bone formation indices: serum osteocalcin, extent of labeled surface, and extent of trabecular number, suggesting that the reduction in bone volume is due most likely to decreased bone formation. The pharmacological evidence presented here provides strong support for the hypothesis that the bone anabolic effect of PGE2 in rats is mediated by the EP4 receptor.
Abbreviations
- PG
- prostaglandin
- PLC
- phospholipase C
- EP4A
- EP4 receptor antagonist [4′-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]
- DMEM
- Dulbecco's modified Eagle's medium
- FBS
- fetal bovine serum
- PBS
- phosphate-buffered saline
- HEK
- human embryonic kidney
- Received February 23, 2001.
- Accepted March 26, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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