Systemic effects of prostaglandin E2 on vertebral trabecular remodeling in beagles used in a healing study (original) (raw)
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Journal of Endocrinology, 2001
Prostaglandin E(2) (PGE(2)) has been shown to exert a bone anabolic effect in young and adult rats. In this study we tested whether it possesses a similar effect on bone formation and bone mass in aging rats. Fifteen-month-old rats were injected daily with either PGE(2) at 5 mg/kg or vehicle for 14 days. PGE(2) treatment stimulated the rate of cancellous bone formation (a approximately 5.5-fold increase in bone formation rate), measured by the incorporation of calcein into bone-forming surfaces at the tibial proximal metaphysis. This effect resulted in increased cancellous bone area (+54%) at the same site. Since PGE(2) treatment resulted in a much higher proportion of bone surface undergoing bone formation and thus lined with osteoblasts, we tested the hypothesis that PGE(2) stimulates osteoblast differentiation from bone marrow precursor cells both in vivo and in vitro. We found that ex vivo cultures of bone marrow stromal cells from rats injected for 2 weeks with PGE(2) at 5 mg/k...
Effects of prostaglandins on rat calvarial bone-cell calcium
Archives of Oral Biology, 1984
Prostaglandin E2 (PGE2) over the concentration range 10(-5)-10(-7) M stimulated calcium uptake in osteoclastic-enriched populations isolated by sequential collagenase digestions of newborn rat calvaria. This effect was on initial calcium uptake occurring at 5 min at 37 degrees C but was not present when isotopic equilibrium was approached (60 min). Prostacyclin (PGI2, PGE1 and PGF2 alpha) stimulated osteoclastic calcium uptake in a similar manner, but with slightly smaller effects than PGE2. Under identical conditions, significant effects of PG were not observed in osteoblastic cells isolated from the same bones by extended collagenase digestions. Combined treatment with PGE2 and parathyroid hormone (PTH) at concentrations which produced no individual effects resulted in a significant increase in calcium uptake in osteoclastic cells. During a 48-h culture period, osteoblastic populations released significantly greater amounts of PGE2 than osteoclastic populations. Pre-incubation for 1 h at 37 degrees C with the prostaglandin cyclo-oxygenase antagonists, indomethacin and flufenamic acid, had no effect on calcium uptake in osteoclastic cells, but resulted in significant decreases in osteoblastic cells. The PGE2-induced increase in calcium uptake on osteoclastic cells was not altered by indomethacin or flufenamic-acid pretreatment. However, after treatment with these inhibitors, a significant response to PGE2 was observed in osteoblastic cells.
Inhibitory and stimulatory effects of prostaglandins on osteoclast differentiation
Calcified Tissue International, 1997
The effect of prostaglandins (PGs) on osteoclast differentiation, an important point of control for bone resorption, is poorly understood. After an initial differentiation phase that lasts at least 4 days, murine monocytes, cocultured with UMR 1 06 osteoblastic cells (in the presence of 1,25-dihydroxyvitamin D 3 ) give rise to tartrate-resistant acid phosphatase (TRAP) positive osteoclast-like cells that are capable of lacunar bone resorption. PGE 2 strongly inhibits TRAP expression and bone resorption in these cocultures. To examine further the cellular mechanisms associated with this inhibitory effect, we added PGE 2 to monocyte/UMR 106 cocultures at specific times before, during, and after this initial 4-day differentiation period. To determine whether this PGE 2 inhibition was dependent on the type of stromal cell supporting osteoclast differentiation, we also added PGE 2 to cocultures of monocytes with ST2 preadipocytic cells.
Calcified Tissue International, 2000
Prostaglandins (PGs) are well known to be important local factors in regulating bone formation and resorption. PGE 2 is a potent stimulator of bone resorption because of enhancing osteoclast formation by its indirect action through stromal cells. However, the direct action of PGE 2 on functionally mature osteoclasts is still controversial. In this study using highly purified rabbit mature osteoclasts, we examined the direct effect of PGE 2 on osteoclastic bone-resorbing activity and its mechanism. PGE 2 inhibited resorption pit formation on a dentine slice by the purified osteoclasts in a dose-and time-dependent manner. The inhibitory effect appeared as early as 4 hours after the PGE 2 addition. Forskolin and 12-0-tetradecanoyl phorbol-13-acetate (TPA), respective activators of adenylate cyclase and protein kinase C, also decreased the osteoclastic boneresorbing activity. PGE 2 increased the content of intracellular cAMP in a dose range effective for the inhibition of bone resorption, whereas the prostanoid did not alter the intracellular level of inositol triphosphate. The inhibition of osteoclastic bone resorption by PGE 2 was amplified and diminished by a cAMP phosphodiesterase inhibitor (isobutyl methylxanthine) and a protein kinase A inhibitor (Rp-cAMP), respectively. Of four different subtypes of PGE 2 receptors (EPs), EP4 mRNA was predominantly expressed in isolated osteoclasts, whereas the other types of EP mRNA were detected in only small amounts. These results suggest that the PGE 2 inhibitory effect was mediated by an adenylate cyclase system coupled with EP4. This possible association of PGE 2 with EP4 in mature osteoclasts was supported by the finding that a specific agonist of EP4 (AE-604) inhibited the bone-resorbing activity and elevated the intracellular cAMP content. However, butaprost, a selective EP2 agonist, also mimicked the PGE 2 effects on isolated osteoclasts although EP2 mRNA expression was minimal. In conclusion, PGE 2 directly inhibits bone-resorbing activity of functionally mature osteoclasts by activation of the adenylate cyclase system, perhaps mainly through EP4.
Endocrinology, 2000
PGE 2 functions as a potent stimulator of bone resorption. The action of PGE 2 is thought to be mediated by some PGE receptor subtypes present in osteoblastic cells. In this study, we examined the involvement of PGE receptor subtypes, EP1, EP2, EP3, and EP4, in PGE 2-induced bone resorption using specific agonists for the respective EPs. In mouse calvaria cultures, EP4 agonist markedly stimulated bone resorption, but its maximal stimulation was less than that induced by PGE 2. EP2 agonist also stimulated bone resorption, but only slightly. EP1 and EP3 agonists did not stimulate it at all. RT-PCR showed that osteoblastic cells isolated from newborn mouse calvaria expressed all of the EPs messenger RNA (mRNA). Both EP2 agonist and EP4 agonist induced cAMP production and the expression of osteoclast differentiation factor (ODF) mRNA in osteoblastic cells. Simultaneous addition of EP2 and EP4 agonists cooperatively induced cAMP production and ODF mRNA expression. In mouse bone marrow cultures, EP2 and EP4 agonists moderately induced osteoclast formation, but the simultaneous addition of the two agonists cooperatively induced it, similar to that by PGE 2. In calvaria culture from EP4 knockout mice, a marked reduction in bone resorption to PGE 2 was found. In EP4 knockout mice, EP4 agonist failed to induce bone resorption, but EP2 agonist slightly, but significantly, induced bone resorption. These findings suggest that PGE 2 stimulates bone resorption by a mechanism involving cAMP and ODF, which is mediated mainly by EP4 and partially by EP2.
Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation
Proceedings of the National Academy of Sciences, 2002
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, PGE 2 induced expression of core-binding factor α1 (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 incr...
Prostaglandin E 2 Strongly Inhibits Human Osteoclast Formation
Endocrinology, 2005
Prostaglandin E 2 (PGE 2 ) enhances osteoclast formation in mouse macrophage cultures treated with receptor activator of nuclear factor-B ligand (RANKL). The effects of PGE 2 on human osteoclast formation were examined in cultures of CD14 ؉ cells prepared from human peripheral blood mononuclear cells. CD14 ؉ cells differentiated into osteoclasts in the presence of RANKL and macrophage colony-stimulating factor. CD14 ؉ cells expressed EP2 and EP4, but not EP1 or EP3, whereas CD14 ؉ cell-derived osteoclasts expressed none of the PGE 2 receptors. PGE 2 and PGE 1 alcohol (an EP2/4 agonist) stimulated cAMP production in CD14 ؉ cells. In contrast to mouse macrophage cultures, PGE 2 and PGE 1 alcohol inhibited RANKL-induced human osteoclast formation in CD14 ؉ cell cultures. H-89 blocked the inhibitory effect of PGE 2 on human osteoclast formation. These results suggest that the
Journal of Bone and Mineral Research, 2009
Cyclic mechanical loading sufficient to engender strains of physiologic magnitude applied to recently excised canine cancellous bone cores in vitro increased the release of prostaglandin E (PGE) and prostacyclin (PGI2, measured as its breakdown product 6-keto-PGF1 alpha), during a 15 minute loading period in which PG levels were measured in perfusing medium at 5 minute intervals. Peak production occurred in the 0-5 minute sample. Mean levels preload compared to during load were PGE, 2.66 and 3.67 ng/ml (p less than 0.002); and 6-keto-PGF1 alpha, 543 and 868 pg/ml (p less than 0.007). The elevated levels then declined to preload levels during the loading period. However, the 5-10 minute but not the 10-15 minute samples still contained levels greater than preload values. A second 15 minute period of load, 1 h following the end of the first, produced smaller increases in the levels of release that were statistically significant only for the first 0-5 minute sample during load (preload compared to load mean values, PGE, 1.09-1.66 ng/ml, p less than 0.02; 6-keto-PGF1 alpha, 401-558 pg/ml, p less than 0.04). Immunolocalization revealed PGE and 6-keto-PGF1 alpha in lining cells and 6-keto-PGF1 alpha but not PGE in osteocytes. Addition to the medium of 1 microM PGE2, approximating the concentration produced by loading, had no significant effect on the specific activity of the extractable RNA fraction labeled with [3H]uridine, whereas 1 microM PGI2 produced an increase similar to that seen previously with loading.(ABSTRACT TRUNCATED AT 250 WORDS)
Prostaglandin E2 enhances alveolar bone formation in the rat mandible
Bone, 2004
Prostaglandin E 2 (PGE 2) induces bone formation in stress-bearing bones. The mandible, a stress-bearing bone, is loaded daily during mastication. The aim of this study was to determine if PGE 2 delivered locally to the mandible over 20 days enhances alveolar bone deposition. In 18 Lewis rats, controlled-release pellets containing PGE 2 were implanted on the buccal aspect on the left-hand side of the mandible, mesial to the root of the first molar. Controlled-release pellets locally delivered 0.1, 0.05, or 0.025 mg/day of PGE 2. The right side of the mandible was used as a matched control for each animal. Six sham-treated animals were implanted with a placebo pellet. On days 7 and 19, animals were injected with the bone markers tetracycline and calcein, respectively. On day 21, animals were sacrificed and undecalcified tissues obtained for morphometrical analysis. Morphometrical measurements were analyzed by paired t test to determine differences between the matched samples and one-way ANOVA to compare the different treatment groups. A significant increase in alveolar bone area was observed in mandibles treated with 0.1 and 0.05 mg/day when compared with matched controls and the placebo group. This was accompanied by a significant increase in alveolar bone height and width. The proportions of double-labeled surface (dLS), the mineral apposition rate (MAR), and bone formation rate (BFR) were significantly increased in mandibles treated with the two higher doses of PGE 2. The proportion of resorptive surface (RS) was significantly reduced in these two groups. It is concluded that PGE 2 induces alveolar bone formation in the mandible when locally delivered at a dose of 0.1 or 0.05 mg/day for 20 days.