Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E 2 promotes both bone resorption and bone formation. By infusing PGE 2 to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist and not agonists specific for other EP subtypes. In culture of bone marrow cells from wild-type mice, PGE2 induced expression of core-binding factor ␣1 (Runx2͞Cbfa1) and enhanced formation of mineralized nodules, both of which were absent in the culture of cells from EP4-deficient mice. Furthermore, administration of the EP4 agonist restored bone mass and strength normally lost in rats subjected to ovariectomy or immobilization. Histomorphometric analysis revealed that the EP4 agonist induced significant increases in the volume of cancellous bone, osteoid formation, and the number of osteoblasts in the affected bone of immobilized rats, indicating that activation of EP4 induces de novo bone formation. In addition, osteoclasts were found on the increased bone surface at a density comparable to that found in the bone of control animals. These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis.B ones undergo continuous remodeling through repeated cycles of destruction and rebuilding (1). This remodeling is mediated by the well balanced actions of osteoclasts, which resorb old bones, and osteoblasts, which form new bones. However, in the elderly, especially in postmenopausal women, the extent of bone resorption far exceeds that of bone rebuilding, resulting in osteoporosis and the associated increases in bone fragility and susceptibility to fractures (2). About 100 million people are estimated to suffer from this debilitating disease worldwide. Several drugs have been developed to treat osteoporosis, with most inhibiting bone resorption and only a few promoting bone formation (3). Such modulation of only one of the two processes in bone remodeling renders these drugs of limited efficacy in restoring the normal balance and bone mass.Recently, significant advances have been made in our understanding of molecular mechanisms of osteoclast and osteoblast differentiation (4), but such knowledge has not been exploited fully to develop a drug that corrects the imbalance and restores normal bone remodeling. Prostaglandins (PGs) are a group of lipid mediators that are produced from arachidonic acid in a variety of tissues under various physiological and pathophysiological conditions and serve to maintain local homeostasis (5). Among them, PGs of the E type work bimodally in bone metabolism (6). PGE 2 potently induces bone resorption in bone organ cultures, whereas repeated injection of this compound in vivo induces bone formation in a variety of animals includ...

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Levels of prostaglandin E(2) (PGE(2)) in human and rodent breast cancers are higher than surrounding normal tissues. PGE(2) exhibits biological activity through binding to membrane receptors, EP(1-4). The present study was designed to investigate the effects of ONO-8711, a newly synthesized selective PGE receptor EP(1) antagonist, on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced breast cancer development. Starting at 7 weeks of age, female Sprague-Dawley (SD) rats were given PhIP (85 mg/kg body weight) by gavage four times weekly for two weeks. Dietary administration of ONO-8711 at 400 or 800 p.p.m. delayed occurrence of breast tumors for 2 or 4 weeks, respectively. At 20 weeks after the last dosing of PhIP, all animals were killed and complete autopsy was made. All breast tumors were diagnosed as invasive ductal adenocarcinomas histopathologically. Administration of ONO-8711 at 800 p.p.m. significantly decreased PhIP-induced breast cancer incidence, multiplicity and volume compared with those of rats fed the control diet (56% versus 79%, P < 0.05, 1.2 versus 2.5, P < 0.05, 0.7 versus 1.4 cm(3), P < 0.01, respectively). Apoptosis was significantly increased in breast cancer cells by feeding of ONO-8711 at 800 p.p.m. of 158% (P < 0.05). EP(1) receptor was detected by reverse transcription-polymerase chain reaction (RT-PCR) in breast cancers, not in normal tissues. These results suggest that EP(1) receptor is associated with breast cancer development and selective PGE receptor EP(1) antagonists may possess chemopreventive effects through the induction of apoptosis without any side effects.

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