Bone cells produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D homeostasis, and a paracrine factor produced in further tissues. Chronic kidney disease and cardiovascular disorders are associated with early elevations of plasma FGF23 levels associated with clinical outcomes. FGF23 production is dependent on many conditions including inflammation. Prostaglandin E₂ (PGE₂) is a major eicosanoid with a broad role in pain, inflammation, and fever. Moreover, it regulates renal blood flow, renin secretion, natriuresis as well as bone formation through prostaglandin E receptor 2 (EP2). Here, we studied the role of PGE₂ and its signaling for the production of FGF23. Osteoblast-like UMR-106 cells were exposed to EP receptor agonists, antagonists or RNAi. Wild type and EP2 knockout mice were treated with stable EP2 agonist misoprostol. Fgf23 or Nurr1 gene expression was determined by quantitative real-time PCR, hormone and further blood parameters by enzyme-linked immunosorbent assay and colorimetric methods. PGE₂ and EP2 agonists misoprostol and butaprost enhanced FGF23 production in UMR-106 cells, effects mediated by EP2 and transcription factor Nurr1. A single dose of misoprostol up-regulated bone Fgf23 expression and FGF23 serum levels in wild type mice with subtle effects on parameters of mineral metabolism only. Compared to wild type mice, the FGF23 effect of misoprostol was significantly lower in EP2-deficient mice. To conclude, PGE₂ signaling through EP2 and Nurr1 induces FGF23 production. Given the broad physiological and pathophysiological implications of PGE₂ signaling, this effect is likely of clinical relevance.

01 Oct 2024·Prostaglandins & Other Lipid Mediators

Effect of PGE2 on TT cells viability and division

Article

Author: Lu, Chien-Chen

Previous studies have shown prostaglandin E2 (PGE2) produced a marked increase in calcitonin secretion in human C-cells derived from medullary thyroid carcinoma. However, it's unclear whether PGE2 can increase the growth of C cells. In this study, we use TT cells as a C cell model to investigate the effect of PGE2 on the growth of C cells. The results revealed that both PGE2 and arachidonic acid (AA) significantly increased the count of TT cells, whereas indomethacin and Dup697 reduced this count. Notably, an increase in the level of AA was associated with an increase in the number of proliferating TT cells, indicating a dose-response relationship. PGE2 and its receptor agonists (sulprostone and butaprost) enhanced the proliferation of TT cells. By contrast, 17-phenyl-trinor-PGE2 exerted no significant effect on TT cell proliferation, whereas L161982 suppressed it. The positive effect of AA on TT cell proliferation was inhibited by indomethacin, NS398, Dup697 (complete inhibition), and SC560. Both PGE2 and AA increased the level of p-STAT5a. The positive effect of AA on p-STAT5a was completely inhibited by Dup697 but not indomethacin, NS398, or SC560. Treatment with indomethacin or Dup697 alone reduced the level of STAT5a in TT cells. AA increased the level of STAT5a, but this effect was inhibited by indomethacin, NS398, and Dup697. Overall, this study confirms the effect of PGE2 on the proliferation of TT cells. This effect is likely mediated through EP2, EP3, and EP4 receptors and associated with an increase in p-STAT5a level within TT cells.

19 Apr 2024·Journal of Molecular Endocrinology

Constitutive internalisation of EP2 differentially regulates G protein signalling

Article

Author: Hanyaloglu, Aylin C ; Parkin, Holly A ; Terzidou, Vasso ; Hye Kim, Sung ; Woodward, David F ; Bennett, Phillip R ; Walker, Abigail R

The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour and cancer. Internalisation and intracellular trafficking are critical for shaping GPCR activity, yet little is known regarding the spatial programming of EP2 signalling and whether this can be exploited pharmacologically. Using three EP2-selective ligands that favour activation of different EP2 pathways, we show that EP2 undergoes limited agonist-driven internalisation but is constitutively internalised via dynamin-dependent, β-arrestin-independent pathways. EP2 was constitutively trafficked to early and very early endosomes (VEE), which was not altered by ligand activation. APPL1, a key adaptor and regulatory protein of the VEE, did not impact EP2 agonist-mediated cAMP. Internalisation was required for ~70% of the acute butaprost- and AH13205-mediated cAMP signalling, yet PGN9856i, a Gαs-biased agonist, was less dependent on receptor internalisation for its cAMP signalling, particularly in human term pregnant myometrial cells that endogenously express EP2. Inhibition of EP2 internalisation partially reduced calcium signalling activated by butaprost or AH13205 and had no effect on PGE2 secretion. This indicates an agonist-dependent differential spatial requirement for Gαs and Gαq/11 signalling and a role for plasma membrane-initiated Gαq/11-Ca2+-mediated PGE2 secretion. These findings reveal a key role for EP2 constitutive internalisation in its signalling and potential spatial bias in mediating its downstream functions. This, in turn, could highlight important considerations for future selective targeting of EP2 signalling pathways.

100 Deals associated with Butaprost

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