Effects of selective prostaglandin EP2 and EP4 receptor agonists on bone resorption and formation in fetal rat organ cultures

Raisz, Lawrence G.; Woodiel, Florence N.

doi:10.1016/s1098-8823(03)00049-2

Cited by 45 publications

(28 citation statements)

References 12 publications

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“…The greater relative effect of PGE 2 , compared to EP2A in POB cultures confirms our previous findings. The persistent effects of PGE 2 in EP2 receptor KO cells presumably reflect an effect mediated by activation of the EP4 receptor which we have shown to stimulate osteoblast differentiation and function [3,4]. A small increase in EP4 receptor mRNA expression in the EP2 KO cells suggests that this may be a compensatory mechanism that could operate in vivo and explain the absence of histologic changes in the bones of EP2 receptor KO animals.…”

Section: Discussionmentioning

confidence: 67%

“…A different selective EP2 receptor agonist has recently been shown to enhance healing of bone defects and increase bone formation when injected locally [13]. Moreover EP2 receptor activation may have the advantage, based on our previous studies in rat organ cultures [3], that it has relatively less stimulatory effect on bone resorption than EP4 activation. Alizarin red staining for osteoblast mineralization in MSC after treatment with EP2A and PGE 2 for 21 days from EP2 receptor WT, Het and KO mice in the presence of NS-398 (0.1 μM).…”

Section: Discussionmentioning

confidence: 99%

“…PGE 2 is a potent stimulator of osteoblast differentiation. In rat calvarial organ cultures selective agonists for the EP4 and EP2 receptors (EP4A and EP2A) increased bone collagen synthesis, while agonists for EP1 and EP3 receptors as well as other prostanoids were ineffective [2,3]. In osteoblastic cells derived from neonatal mouse calvariae the effects of PGE 2 on alkaline phosphatase activity and osteocalcin gene expression could be mimicked by EP4A, while EP2A was less effective [4].…”

Section: Introductionmentioning

confidence: 99%

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Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist

Choudhary

Alander

Zhan

et al. 2008

Prostaglandins & Other Lipid Mediators

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Studies using prostaglandin E receptor (EP) agonists indicate that prostaglandin (PG) E 2 can have anabolic effects through both EP4 and EP2 receptors. We previously found that the anabolic response to a selective EP4 receptor agonist (EP4A, Ono Pharmaceutical) was substantially greater than to a selective EP2 receptor agonist (EP2A) in cultured murine calvarial osteoblastic cells. To further define the role of the EP2 receptor in PG-mediated effects on bone cells, we examined the effects of EP2A and PGE 2 on both calvarial primary osteoblasts (POB) and marrow stromal cells (MSC) cultured from mice with deletion of one (Het) or both (KO) alleles of the EP2 receptor compared to their wild type (WT) littermates. Deletion of EP2 receptor was confirmed by quantitative real-time PCR, Western Blot and immunohistochemistry. The one month old mice used to provide cells in these studies did not show any significant differences in their femurs by static histomorphometry. EP2A was found to enhance osteoblastic differentiation as measured by alkaline phosphatase mRNA expression and activity as well as osteocalcin mRNA expression and mineralization in the WT cell cultures from both marrow and calvariae. The effects were somewhat diminished in cultures from Het mice and abrogated in cultures from KO mice. PGE 2 effects were greater than those of EP2A, particularly in POB cultures and were only moderately diminished in Het and KO cell cultures. We conclude that activation of the EP2 receptor is able to enhance differentiation of osteoblasts, that EP2A is a true selective agonist for this receptor and that PGE 2 has an additional anabolic effect likely mediated by the EP4 receptor.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist

Choudhary

Alander

Zhan

et al. 2008

Prostaglandins & Other Lipid Mediators

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“…Previous reports have demonstrated that EP2 selective agonists are anabolic in organ culture and in vivo (7,9,10). Yet we only observed small effects of EP2A in the present study.…”

Section: Discussionmentioning

confidence: 96%

“…Recent studies using animals with deletion of either the EP2 or EP4 receptors or using selective agonists for these receptors have suggested that both EP2 and EP4 can mediate anabolic responses to PGE 2 (4)(5)(6)(7)(8)(9)(10), although the EP1 receptor may also be involved (11). Activation of EP2 and EP4 receptors increases cAMP and can also induce COX-2, which can result in auto-amplification of PGE 2 signaling (12).…”

Section: Introductionmentioning

confidence: 99%

Effects of selective prostaglandins E2 receptor agonists on cultured calvarial murine osteoblastic cells

Alander

Raisz

2006

Prostaglandins & Other Lipid Mediators

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We compared the direct effects of selective EP4 and EP2 receptor agonists (EP4A and EP2A) with prostaglandin E 2 (PGE 2 ) on the differentiation of cultured murine calvarial osteoblastic cells. EP4A increased alkaline phosphatase activity and osteocalcin mRNA levels in these cultures similar to PGE 2 . This effect was seen with both "direct plating" immediately after isolating the cells, or "indirect plating" in which the cells were grown to confluence and replated. EP2A had a smaller effect, significant only in "indirect plating" experiments. All three agents decreased the DNA and protein content in indirect plating experiments, but not in direct plating experiments. We conclude that the anabolic effect of PGE 2 in calvarial osteoblastic cell cultures is largely mediated by activation of the EP4 receptor, while activation of the EP2 receptor is less effective.

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Crosstalk between the COX2‐PGE2‐EP4 signaling pathway and primary cilia in osteoblasts after mechanical stimulation

Zhu

Yang

et al. 2020

Journal Cellular Physiology

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Primary cilia have been found to function as mechanosensors in low-magnitude high-frequency vibration (LMHFV)-induced osteogenesis. The PGE2 also regulates bone homeostasis and mechanical osteogenesis through its receptor EP4 signaling, but its involvement in LMHFV-induced or in primary cilia-induced osteogenesis has not been investigated. We hypothesized that LMHFV stimulates osteoblast (OB) differentiation by activating the COX2-PGE2-EP pathway in a manner dependent on primary cilia and that primary cilia are also affected by the PGE2 pathway. In this study, through western blot analysis, RNA interference, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and cytochemical staining, we observed that COX2, mPGES-1, and PGE2 levels were markedly elevated in cells treated with LMHFV and were greatly decreased in LMHFV-treated cells following IFT88 silencing. EP4 expression was significantly increased in OBs following LMHFV treatment, but IFT88 silencing significantly blocked this increase. EP4 localized to the bases of primary cilia. LMHFV reduced the length and abundance of primary cilia, but the cells could self-repair their primary cilia after mechanical damage. EP4 antagonism significantly blocked the LMHFV-induced increase in IFT88 expression and blocked the recovery of primary cilia length and the proportion of cells with primary cilia. In addition, COX2 or EP4 antagonism disrupted LMHFV-induced osteogenesis. These results demonstrate the integration of and crosstalk between primary cilia and the COX2-PGE2-EP4 signaling pathway under mechanical stimulation.

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Effects of selective prostaglandin EP2 and EP4 receptor agonists on bone resorption and formation in fetal rat organ cultures

Cited by 45 publications

References 12 publications

Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist

Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist

Effects of selective prostaglandins E2 receptor agonists on cultured calvarial murine osteoblastic cells

Crosstalk between the COX2‐PGE2‐EP4 signaling pathway and primary cilia in osteoblasts after mechanical stimulation

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