Browsing by Person "Feger, Martina"

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Prostaglandin E2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production
(2024) Feger, Martina; Hammerschmidt, Katharina; Liesche, lona; Rausch, Steffen; Alber, Jana; Föller, Michael
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.
Short‐term fasting of mice elevates circulating fibroblast growth factor 23 (FGF23)
(2023) Feger, Martina; Alber, Jana; Strotmann, Jörg; Grund, Andrea; Leifheit‐Nestler, Maren; Haffner, Dieter; Föller, Michael
Aims: Phosphate and vitamin D homeostasis are controlled by fibroblast growth factor 23 (FGF23) from bone suppressing renal phosphate transport and enhancing 24-hydroxylase (Cyp24a1), thereby inactivating 1,25(OH)2D3. Serum FGF23 is correlated with outcomes in several diseases. Fasting stimulates the production of ketone bodies. We hypothesized that fasting can induce FGF23 synthesis through the production of ketone bodies. Methods: UMR106 cells and isolated neonatal rat ventricular myocytes (NRVM) were treated with ketone body β-hydroxybutyrate. Mice were fasted overnight, fed ad libitum, or treated with β-hydroxybutyrate. Proteins and further blood parameters were determined by enzyme-linked immunoassay (ELISA), western blotting, immunohistochemistry, fluorometric or colorimetric methods, and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). Results: β-Hydroxybutyrate stimulated FGF23 production in UMR106 cells in a nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB)-dependent manner, and in NRVMs. Compared to fed animals, fasted mice exhibited higher β-hydroxybutyrate and FGF23 serum levels (based on assays either detecting C-terminal or intact, biologically active FGF23 only), cardiac, pancreatic, and thymic Fgf23 and renal Cyp24a1 expression, and lower 1,25(OH)2D3 serum concentration as well as renal Slc34a1 and αKlotho (Kl) expression. In contrast, Fgf23 expression in bone and serum phosphate, calcium, plasma parathyroid hormone (PTH) concentration, and renal Cyp27b1 expression were not significantly affected by fasting. Conclusion: Short-term fasting increased FGF23 production, as did administration of β-hydroxybutyrate, effects possibly of clinical relevance in view of the increasing use of FGF23 as a surrogate parameter in clinical monitoring of diseases. The fasting state of patients might therefore affect FGF23 tests.
Tachysterol2 increases the synthesis of fibroblast growth factor 23 in bone cells
(2022) Ewendt, Franz; Kotwan, Julia; Ploch, Stefan; Feger, Martina; Hirche, Frank; Föller, Michael; Stangl, Gabriele I.
Tachysterol2 (T2) is a photoisomer of the previtamin D2 found in UV-B-irradiated foods such as mushrooms or baker’s yeast. Due to its structural similarity to vitamin D, we hypothesized that T2 can affect vitamin D metabolism and in turn, fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone that is transcriptionally regulated by the vitamin D receptor (VDR). Initially, a mouse study was conducted to investigate the bioavailability of T2 and its impact on vitamin D metabolism and Fgf23 expression. UMR106 and IDG-SW3 bone cell lines were used to elucidate the effect of T2 on FGF23 synthesis and the corresponding mechanisms. LC-MS/MS analysis found high concentrations of T2 in tissues and plasma of mice fed 4 vs. 0 mg/kg T2 for 2 weeks, accompanied by a significant decrease in plasma 1,25(OH)2D and increased renal Cyp24a1 mRNA abundance. The Fgf23 mRNA abundance in bones of mice fed T2 was moderately higher than that in control mice. The expression of Fgf23 strongly increased in UMR106 cells treated with T2. After Vdr silencing, the T2 effect on Fgf23 diminished. This effect is presumably mediated by single-hydroxylated T2-derivatives, since siRNA-mediated silencing of Cyp27a1, but not Cyp27b1, resulted in a marked reduction in T2-induced Fgf23 gene expression. To conclude, T2 is a potent regulator of Fgf23 synthesis in bone and activates Vdr. This effect depends, at least in part, on the action of Cyp27a1. The potential of oral T2 to modulate vitamin D metabolism and FGF23 synthesis raises questions about the safety of UV-B-treated foods.
Up-regulation of fibroblast growth factor 23 gene expression in UMR106 osteoblast-like cells with reduced viability
(2021) Münz, Sina; Feger, Martina; Edemir, Bayram; Föller, Michael
Fibroblast growth factor 23 (FGF23) controls vitamin D and phosphate homeostasis in the kidney and has additional paracrine effects elsewhere. As a biomarker, its plasma concentration is associated with progression of inflammatory, renal, and cardiovascular diseases. Major stimuli of FGF23 synthesis include active vitamin D and inflammation. Antineoplastic chemotherapy treats cancer by inducing cellular damage ultimately favoring cell death (apoptosis and necrosis) and causing inflammation. Our study explored whether chemotherapeutics and other apoptosis inducers impact on Fgf23 expression. Experiments were performed in osteoblast-like UMR106 cells, Fgf23 gene expression and protein synthesis were determined by qRT-PCR and ELISA, respectively. Viability was assessed by MTT assay and NFκB activity by Western Blotting. Antineoplastic drugs cisplatin and doxorubicin as well as apoptosis inducers procaspase-activating compound 1 (PAC-1), a caspase 3 activator, and serum depletion up-regulated Fgf23 transcripts while reducing cell proliferation and viability. The effect of cisplatin on Fgf23 transcription was paralleled by Il-6 up-regulation and NFκB activation and attenuated by Il-6 and NFκB signaling inhibitors. To conclude, cell viability-decreasing chemotherapeutics as well as apoptosis stimulants PAC-1 and serum depletion up-regulate Fgf23 gene expression. At least in part, Il-6 and NFκB may contribute to this effect.