Biomedical subjects

Yukihiko Sugimoto

Publications and source records attributed to Yukihiko Sugimoto.

At least 19 recordsLinked to original sources

PubMed2004

Microarray evaluation of EP4 receptor-mediated prostaglandin E2 suppression of 3T3-L1 adipocyte differentiation.

Prostaglandin E(2) (PGE(2)) has been shown to negatively regulate adipogenesis. To explore to what extent PGE(2) inhibits the differentiation of cells to adipocytes and to examine whether its effect could be due to EP4 receptor signaling, we used microarrays to analyze the gene expression profiles of 3T3-L1 cells exposed to a differentiation cocktail supplemented with PGE(2), AE1-329 (an EP4 agonist), or vehicle. The differentiation-associated responses in genes such as adipocytokines and enzymes related to lipid metabolism were largely weakened upon PGE(2) treatment. In particular, the expression of peroxisome proliferator activated receptor-gamma and CCAAT/enhancer binding protein-alpha, genes playing a central role in adipogenesis, was greatly suppressed. PGE(2) appears to be ineffective to a subclass of insulin target genes such as hexokinase 2 and phosphofructokinase. Similar responses were produced in the differentiation-associated genes upon AE1-329 treatment. These results suggest that PGE(2) inhibits a crucial step of the adipocyte differentiation process by acting on the EP4 receptor in 3T3-L1 cells.

3T3 Cells↗

PubMed2004

Prostanoid EP4 receptor is involved in suppression of 3T3-L1 adipocyte differentiation.

Prostaglandins (PGs) have been shown to play various roles in adipogenesis. In this study, we investigated on which PGE receptor subtypes are involved in the inhibition of 3T3-L1 preadipocyte differentiation. The triglyceride content of cells, used as an index of differentiation, was decreased when PGE(2), the FP-agonist fluprostenol or dibutyryl cAMP, was exogenously added to differentiation cocktails. 3T3-L1 preadipocyte cells express mRNAs for the prostanoid EP4, FP, and IP receptors. PGE(2) and the EP4 agonist AE1-329 increased cAMP levels in preadipocytes in a dose-dependent manner. AE1-329 suppressed the expression induction of differentiation marker genes such as resistin and peroxisome proliferator-activated receptor-gamma. The inhibitory effect of PGE(2) but not that of fluprostenol was reversed by the addition of the EP4 antagonist AE3-208. AE3-208 mimicked the differentiation-promoting effects of indomethacin. These results suggest that the EP4 receptor mediates the suppressive action of PGE(2) in 3T3-L1 adipocyte differentiation.

3T3 Cells↗

PubMed2004

Expression of L-histidine decarboxylase in granules of elicited mouse polymorphonuclear leukocytes.

Infiltrating polymorphonuclear leukocytes (PMN) in the peritoneal cavity were found to express L-histidine decarboxylase (HDC), the rate-limiting enzyme of histamine synthesis, in a csein-induced peritonitis model. Expression of HDC was detected in the elicited PMN, but not in the peripheral blood leukocytes. The peritoneal lavage fluids in this model were found to augment histamine synthesis in PMN isolated from the bone marrow. Rapid post-translational processing of HDC was observed in PMN, and the dominant form of HDC was the mature 53-kDa form, which was found to co-localize with a granule enzyme, matrix metalloproteinase-9 (MMP-9). Treatment of PMN with the phorbol ester PMA, which stimulates the release of MMP-9, did not liberate the granular HDC. Immunofluorescence studies using an anti-HDC antibody strongly suggested that HDC is bound to the cytosolic side of the granule membranes. These observations suggest that HDC is induced upon infiltration of PMN into the mouse peritoneal cavity and that histamine is synthesized by HDC attached to the granule membranes of PMN.

Animals↗

PubMed2003

A cluster of aromatic amino acids in the i2 loop plays a key role for Gs coupling in prostaglandin EP2 and EP3 receptors.

To assess the structural requirements for G(s) coupling by prostaglandin E receptors (EPs), the G(s)-coupled EP2 and G(i)-coupled EP3beta receptors were used to generate hybrid receptors. Interchanging of the whole i2 loop and its N-terminal half (i2N) had no effect on the binding of both receptors expressed in HEK293 cells. Agonist-induced cAMP formation was observed in wild type EP2 but not in the i2 loop- or i2N-substituted EP2. Wild type EP3beta left cAMP levels unaffected, whereas i2 loop- and i2N-substituted EP3 gained agonist-induced adenylyl cyclase stimulation. In EP2, the ability to stimulate cAMP formation was lost by mutation of Tyr(143) into Ala but retained by mutations into Phe, Trp, and Leu. Consistent with this observation, substitution of the equivalent His(140) enabled EP3beta to stimulate cAMP formation with the rank order of Phe > Tyr > Trp > Leu. The point mutation of His(140) into Phe was effective in another EP3 variant in which its C-terminal tail is different or lacking. Simultaneous mutation of the adjacent Trp(141) to Ala but not at the following Tyr(142) weakened the acquired ability to stimulate cAMP levels in the EP3 mutant. Mutation of EP2 at adjacent Phe(144) to Ala but not at Tyr(145) reduced the efficiency of agonist-induced cAMP formation. In Chinese hamster ovary cells stably expressing G(s)-acquired EP3 mutant, an agonist-dependent cAMP formation was observed, and pertussis toxin markedly augmented cAMP formation. These results suggest that a cluster of hydrophobic aromatic amino acids in the i2 loop plays a key role for G(s) coupling.

Amino Acid Sequence↗

PubMed2003

Functional domains essential for Gs activity in prostaglandin EP2 and EP3 receptors.

The interaction of cell surface hormone receptors with heterotrimeric G proteins is crucial for hormonal actions. The domains of the receptor, which interact with and activate G protein, have been extensively studied. However, precise molecular mechanisms underlying regulation of the receptor-induced G protein activation are still poorly understood. Prostaglandin E(2) (PGE(2)) receptors comprise of four subtypes, EP1, EP2, EP3 and EP4. Among them, EP2 and EP4 couple to Gs and EP3 to Gi. To assess the functional domains essential for Gs activation in prostanoid receptors, EP2, EP3beta and each intracellular loop- (IC-) interchanged EP2/EP3 chimeras were tested for agonist binding and functional responses. In EP2 receptor, substitution of IC1 or IC3 resulted in loss of binding activity, while substitution of IC2, N- (IC2N) or C-terminal half region of IC2 (IC2C) had no effects on the binding activity. Wild-type EP2 and IC2C-substituted EP2 showed agonist-induced Gs activity, but IC2- and IC2N-substituted EP2 failed to elicit Gs activity upon agonist stimulation. On the other hand, in EP3 receptor substitution of IC1 resulted in loss of PGE(2) binding, while substitution of IC2, IC3, IC2N or IC2C had no effects on binding activity. Wild-type EP3beta, IC3- or IC2C-substituted EP3 failed to show Gs activity upon agonist stimulation, but IC2- or IC2N-substituted EP3 chimera showed agonist-dependent Gs activity. These results indicated that the second intracellular loop of the EP2 plays an essential role in activation of Gs.

Animals↗

PubMed2003

Characteristics of thermoregulatory and febrile responses in mice deficient in prostaglandin EP1 and EP3 receptors.

Previous studies have disagreed about whether prostaglandin EP1 or EP3 receptors are critical for producing febrile responses. We therefore injected lipopolysaccharide (LPS) at a variety doses (1 microg kg(-1)-1 mg kg(-1)) intraperitoneally (i.p.) into wild-type (WT) mice and mice lacking the EP1 or the EP3 receptors and measured changes in core temperature (Tc) by using telemetry. In WT mice, i.p. injection of LPS at 10 microg kg(-1) increased Tc about 1 degrees C, peaking 2 h after injection. At 100 microg kg(-1), LPS increased Tc, peaking 5-8 h after injection. LPS at 1 mg kg(-1) decreased Tc, reaching a nadir at 5-8 h after injection. In EP1 receptor knockout (KO) mice injected with 10 microg kg(-1) LPS, only the initial (< 40 min) increase in Tc was lacking; with 100 microg kg(-1) LPS the mice showed no febrile response. In EP3 receptor KO mice, LPS decreased Tc in a dose- and time-dependent manner. Furthermore, in EP3 receptor KO mice subcutaneous injection of turpentine did not induce fever. Both EP1 and EP3 receptor KO mice showed a normal circadian cycle of Tc and brief hyperthermia following psychological stress (cage-exchange stress and buddy-removal stress). The present study suggests that both the EP1 and the EP3 receptors play a role in fever induced by systemic inflammation but neither EP receptor is involved in the circadian rise in Tc or psychological stress-induced hyperthermia in mice.

Animals↗

PubMed2003

Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two prostaglandin E2 receptor subtypes, EP3 and EP4.

In this study, we investigated the role of PGE(2) in mouse mastocytoma P-815 cell adhesion to extracellular matrix proteins (ECMs) in vitro. We report that PGE(2) accelerated ProNectin F(TM) (a proteolytic fragment of fibronectin)-mediated adhesion, which was abolished by addition of the GRGDS peptide, an inhibitor of the RDG binding site of ProNectin F(TM). We show that the cAMP level and cAMP-regulated protein kinase (PKA) activity are critical mediators of this PGE(2) effect, because the cell-permeable cAMP analogue 8-Br-cAMP accelerated P-815 cell adhesion to ProNectin F(TM) and the pharmacological inhibitor of PKA, H-89, blocked PGE(2)-mediated adhesion. Consistent with mRNA expression of the G(s)-coupled EP4- and G(i)-coupled EP3-PGE receptor subtypes, P-815 cell adhesion was accelerated by treatment with a selective EP4 agonist, ONO-AE1-329, but not a selective EP1/EP3 agonist, sulprostone. However, simultaneous treatment with ONO-AE1-329 and sulprostone resulted in augmentation of both the cAMP level and cell adhesion. The augmentation of EP3-mediated cAMP synthesis was dose-dependent, without affecting the half-maximal concentration for EP4-mediated G(s)-activity, which was inhibited by a G(i) inhibitor, pertussis toxin. In conclusion, these findings suggest that PGE(2) accelerates RGD-dependent adhesion via cooperative activation between EP3 and EP4 and contributes to the recruitment of mast cells to the ECM during inflammation.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2003

Expression of the prostaglandin F receptor (FP) gene along the mouse genitourinary tract.

PGF(2alpha) is one of the major prostanoids produced by the kidney. The cellular effects of PGF(2alpha) are mediated by a G protein-coupled transmembrane receptor designated the FP receptor. Both in situ hybridization and beta-galactosidase knocked into the endogenous FP locus were used to determine the cellular distribution of the mouse FP receptor. Specific labeling was detected in the kidney, ovary, and uterus. Abundant FP expression in ovarian follicles and uterus is consistent with previous reports of failed parturition in FP-/- mice. In the kidney, coexpression of the mFP mRNA with the thiazide-sensitive cotransporter defined its expression in the distal convoluted tubule (DCT). FP receptor was also present in aquaporin-2-positive cortical collecting ducts (CCD). No FP mRNA was detected in glomeruli, proximal tubules, or thick ascending limbs. Intrarenal expression of the FP receptor in the DCT and CCD suggests an important role for the FP receptor regulating water and solute transport in these segments of the nephron.

Animals↗

PubMed2003

Role of prostaglandin H2 synthase 2 in murine parturition: study on ovariectomy-induced parturition in prostaglandin F receptor-deficient mice.

To determine the prostaglandin (PG) H2 synthase (generally referred to as cyclooxygenase [COX]) isozyme responsible for producing uterotonic PGs during parturition, we used PGF2alpha receptor-deficient mice, which exhibit parturition failure due to impaired withdrawal of serum progesterone at term. On ovariectomy-induced parturition in these mice, uterine COX-2 mRNA expression was drastically induced in the myometrium, whereas COX-1 mRNA expression in the endometrial epithelium decreased. The concomitant administration of progesterone with ovariectomy resulted in a delay in parturition and the disappearance of both the increase in COX-2 mRNA and the decrease in COX-1 mRNA. Thus, the expression of myometrial COX-2 and the occurrence of parturition are closely associated in this model. Furthermore, administration of the COX-nonselective inhibitor, indomethacin, or the COX-2-selective inhibitor, Dup-697 or JTE-522, effectively delayed ovariectomy-induced parturition in these mice. These findings suggest that COX-2-derived PGs contribute to the onset of parturition after the decrease in serum progesterone level.

Animals↗

PubMed2003

Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth.

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3(-/-)) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3(-/-), in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3(-/-), compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3(-/-). These results demonstrate significance of host stromal PGE(2)-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

Animals↗

PubMed2003

Apoptosis and related proteins in placenta of intrauterine fetal death in prostaglandin f receptor-deficient mice.

The present study investigated whether the increase of apoptosis in the placenta is associated with intrauterine fetal death in prostaglandin F receptor-deficient mice. Apoptosis was demonstrated within placental and decidual tissue by the TUNEL method. The majority of apoptosis was found in syncytiotrophoblast tissues. Enhanced TUNEL-positive staining in the syncytiotrophoblast layer was scattered in the placental tissues in clusters of apoptotic cells in the death group. Marked TUNEL-positive cells were identified in decidua of both groups. The rate of apoptosis in the placenta and decidua in the death group was higher than that in the survival group (P < 0.05). Immunohistochemical analysis showed that the level of active caspase-3 protein expression in the placenta in the death group was much higher than that in the survival group. The level of Bcl-2 protein expression in the placenta in the death group was much lower than that in the survival group. Western blot analysis demonstrated that increased expression of the active form of caspase-3 was detected in the placenta and decidua in the death group compared with that in the survival group. In contrast, a decrease in the expression of Bcl-2 was detected in the placenta and decidua in the death group compared with that in the survival group. Enhanced expression of Bax:Bcl-2 ratio was detected in placenta and decidua in the death group compared with that in the survival group. Thus, significantly increased apoptosis in the mouse placenta and decidua might be involved in the pathophysiologic mechanism of intrauterine fetal death.

Animals↗

PubMed2003

Functional evidence for interaction between prostaglandin EP3 and kappa-opioid receptor pathways in tactile pain induced by human immunodeficiency virus type-1 (HIV-1) glycoprotein gp120.

HIV-1 glycoprotein gp120 administered intrathecally induces tactile pain (allodynia) in animals. In the present study, we investigated the mechanism of gp120-induced allodynia and possible functional connections with factors modulating pain transmission at the spinal level. Gp120 evoked allodynia in a dose-dependent manner with the maximum effect at 1 pg/mouse, and stimulated a rapid increase in intracellular free Ca2+ concentration ([Ca2+]i) in the dorsal horn cells of the spinal cord. These responses evoked by gp120 were blocked by galactocerebroside. The gp120-induced allodynia was also attenuated by the non-steroidal anti-inflammatory drug indomethacin, which inhibits prostaglandin synthesis, and did not develop in mice lacking the EP3 prostaglandin E receptor subtype (EP3(-/-)). Pretreatment of spinal slices with indomethacin dose-dependently decreased the percentage of the cells that showed increased [Ca2+]i in response to gp120, and the decrease was reversed by addition of the selective EP3 agonist ONO-AE-248. The kappa-opioid agonist U-50,488 significantly enhanced the gp120-stimulated increase in [Ca2+]i in spinal slices prepared from EP3(-/-) mice, and the simultaneous addition of U-50,488 with gp120 reproduced the gp120-induced allodynia in EP3(-/-) mice. These results suggest that gp120 induced allodynia by increasing [Ca2+]i, concomitant with activation of prostanoid EP3 and kappa-opioid receptors in the spinal cord.

Animals↗

PubMed2003

Identification and characterization of a novel progesterone receptor-binding element in the mouse prostaglandin E receptor subtype EP2 gene.

BACKGROUND: Gene expression of prostaglandin E receptor EP2 is induced in the luminal epithelium of the mouse uterus during peri-implantation period (day-5 of pseudopregnancy), suggesting the involvement of progesterone and its receptor (PR) in this expression. However it remains unclear whether PR affects EP2 gene expression through its binding. RESULTS: We investigated transcriptional regulation of EP2 gene expression with reporter gene analysis using HeLa cells with or without expression of the PR. The 5'-flanking region (-3260 to -27, upstream of the translation initiation site) exhibited progesterone-induced promoter activation and basal promoter activity in the presence of PR. Using successive deletion analysis, we determined the six regulatory regions in the EP2 gene. Three regions were found to be involved in progesterone-induced promoter activation, whereas the other three regions were involved in basal promoter activity in the presence of PR. We identified a novel PR-binding sequence, 5'-G(G/A)CCGGA-3', in the two basal promoter regions and Sp1- and Sp3-binding in the other basal promoter region. CONCLUSIONS: We identified a novel PR-binding sequence, which may be involved in the regulation of basal promoter activity in the EP2 gene.

5' Flanking Region↗

PubMed2003

Expression of messenger RNA for prostaglandin E receptor subtypes EP4/EP2 and cyclooxygenase isozymes in mouse periovulatory follicles and oviducts during superovulation.

Prostaglandin (PG) E(2) is synthesized from arachidonic acid by cyclooxygenase (COX) and acts as a regulator in ovulation and fertilization reactions. We present the temporal and regional expression patterns of mRNAs for the two Gs-coupled PGE receptors, EP2 and EP4, and for COX-1 and COX-2 in mouse periovulatory follicles and oviducts during superovulation. Analysis using reverse transcription polymerase chain reaction revealed that the mouse ovaries express a significant amount of EP4 mRNA in addition to EP2 mRNA during superovulation. In situ hybridization results revealed that the signals for EP4 mRNA were localized mostly to oocytes in the preantral follicles. Three hours after hCG injection, the signals for EP4 and EP2 mRNA were present in both granulosa and cumulus cells. However, 9 h after hCG injection, just before ovulation, the signals for EP4 mRNA were still detectable in both cell types, whereas those for EP2 mRNA were found only in cumulus cells. COX-2 mRNA expression was present in both granulosa and cumulus cells at 3 h but was present only in cumulus cells at 9 h. COX-1 mRNA expression was not found in granulosa cells at 3 h but was found in these cells at 9 h. In the oviduct, the expression of EP4 and COX-1 mRNA was localized to epithelial cells, whereas expression of EP2 mRNA was localized to the smooth muscle layer. The tightly regulated expression of both EP2 and EP4 in the preovulatory follicles may reflect the essential role of PGE(2) in the ovulation process.

Animals↗

PubMed2003

Prostaglandin E receptors in bile ducts of hepatolithiasis patients and the pathobiological significance for cholangitis.

BACKGROUND & AIMS: In hepatolithiasis, chronic proliferative cholangitis may influence the progression of the disease. Prostaglandin (PG) E(2) experimentally causes morphologic changes to intrahepatic bile ducts, analogous to the changes found in cholangitis. This study was designed to gain an understanding of the involvement of PGE(2) and PGE receptor (EP) subtypes in the development of cholangitis. METHODS: The expression levels of secretory-type group IIA phospholipase A(2) (sPLA(2)-IIA) and cyclooxygenase (COX)-2 as well as EP subtypes were determined in the bile ducts with change of cholangitis. In in vitro experiments, growth promotion and mucin secretagogue properties of biliary epithelial cells in response to EP-selective agonists or antagonists were studied. RESULTS: The messenger RNA (mRNA) level of sPLA(2)-IIA and the protein and mRNA levels of COX-2 were significantly increased in the bile ducts of patients with hepatolithiasis compared with the levels of the bile ducts of control subjects. These changes were associated with a concomitant increase in PGE(2) and total mucin concentrations in the bile. The mRNAs of EP subtypes EP(2), EP(3), and EP(4) but not EP(1) were amplified in the bile ducts. Treatment with an EP(4)-selective agonist (ONO-AE1-329) caused a dose-dependent increase in DNA synthesis, colony number, and mucin secretion in the cells. Conversely, treatment with an EP(4)-selective antagonist (ONO-AE3-208) abolished the biological effects of PGE(2) on the cells. CONCLUSIONS: In hepatolithiasis, an enhanced synthesis of sPLA(2)-/COX-2-derived PGE(2) and its actions mediated via the EP(4) receptor in the bile ducts may be of pathobiological significance for chronic proliferative cholangitis.

Aged↗

PubMed2002

Possible coupling of prostaglandin E receptor EP(1) to TRP5 expressed in Xenopus laevis oocytes.

We previously reported that the prostaglandin E(2) (PGE(2)) receptor subtype EP(1) is coupled to intracellular Ca(2+) mobilization in CHO cells, which is dependent on extracellular Ca(2+) in a pertussis toxin-insensitive manner [H. Katoh, et al., Biochim. Biophys. Acta 1244 (1995) 41-48]. However, it remains unknown about the signal transduction involved in this response. To investigate the mechanism regulating Ca(2+) mobilization mediated by EP(1) receptors in detail, we performed a series of experiments using the Xenopus laevis oocyte expression system and found that endogenous G(q) and/or G(11), and not G(i1) is involved in the Ca(2+) mobilization induced by PGE(2). We further investigated the receptor-activated Ca(2+) channel (RACC)-related response by introducing mRNA for mouse transient receptor potential 5 (TRP5), a possible candidate for the RACC, and found effective coupling between them. These results suggest that the EP(1) receptors induce Ca(2+) mobilization via G(q) and/or G(11) and Ca(2+) influx via TRP.

Animals↗

PubMed2002

Apoptosis and related proteins during parturition in prostaglandin F receptor-deficient mice.

This study investigated whether apoptosis and related proteins are involved in parturition by comparative observation of FP-deficient mice without labor and wild type mice with vaginal delivery. We examined the expression of apoptosis, Fas, FasL, active caspase-3 and bcl-2 proteins in the amnion, placenta and decidua. DNA laddering in the amnion, placenta and decidua tissue did not significantly differ between FP-deficient and wild type mice on day 18 of pregnancy. Similar TUNEL staining results were found in all tissues of FP-deficient mice compared with those of wild type mice. A higher intensity of apoptotic cells was found in the decidua basalis. The index of TUNEL-positive cells were not significantly different in the amnion, placenta and decidua of FP-deficient mice compared with that of wild type mice on day 18 of pregnancy. Specific bands for Fas were clearly observed in the amnion, placenta and decidua tissue. FasL specific bands were observed in the placenta and decidua, but a few in amnion tissue. A great number of active caspase-3 specific bands were detected in decidua, while a few such bands were detected in the placenta and few bands in the amniotic tissue. Bands for bcl-2 were detected in the amnion, placenta and decidua tissue. The weakest band was in decidual tissue. Fas, FasL, active caspase-3, and bcl-2 specific bands did not show any significant differences between the two groups. These findings demonstrate that apoptosis, Fas, FasL, caspase-3, and Bcl-2 occur in mouse term placenta that is not involved in parturition.

Amnion↗

PubMed2002

Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.

Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E2 promotes both bone resorption and bone formation. By infusing PGE2 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 alpha1 (Runx2/Cbfa1) 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.

Animals↗