Institut für Biologie

Permanent URI for this collectionhttps://hohpublica.uni-hohenheim.de/handle/123456789/81

Browse

Now showing 1 - 3 of 3

Lactic acid induces fibroblast growth factor 23 (FGF23) production in UMR106 osteoblast-like cells
(2021) Alber, Jana; Föller, Michael
Endocrine and paracrine fibroblast growth factor 23 (FGF23) is a protein predominantly produced by bone cells with strong impact on phosphate and vitamin D metabolism by targeting the kidney. Plasma FGF23 concentration early rises in kidney and cardiovascular diseases correlating with progression and outcome. Lactic acid is generated in anaerobic glycolysis. Lactic acidosis is the consequence of various physiological and pathological conditions and may be fatal. Since FGF23 production is stimulated by inflammation and lactic acid induces pro-inflammatory signaling, we investigated whether and how lactic acid influences FGF23. Experiments were performed in UMR106 osteoblast-like cells, Fgf23 mRNA levels estimated from quantitative real-time polymerase chain reaction, and FGF23 protein determined by enzyme-linked immunosorbent assay. Lactic acid dose-dependently induced Fgf23 gene expression and up-regulated FGF23 synthesis. Also, Na+-lactate as well as formic acid and acetic acid up-regulated Fgf23. The lactic acid effect was significantly attenuated by nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB) inhibitors wogonin and withaferin A. Lactic acid induces FGF23 production, an effect at least in part mediated by NFκB. Lactic acidosis may, therefore, be paralleled by a surge in plasma FGF23.
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.
Regulation of fibroblast growth factor 23 (FGF23) in metabolic derangement
(2024) Alber, Jana; Föller, Michael
Increased incidence of metabolic syndrome is attributable to Western dietary patterns. Metabolic syndrome enhances risk of developing diabetes mellitus type 2 or cardiovascular diseases, which are associated with lactic acidosis, diabetic ketoacidosis and hyperhomocysteinemia. Increased lactate, ketone body or homocysteine levels are therefore relevant indicators of impaired metabolism and pathogenesis. FGF23 is an important regulator of calcitriol and phosphate homeostasis, and is predominantly synthesized in bone cells. Synthesis of FGF23 is regulated by various mechanisms including insulin/IGF1, mTOR, AMPK, PPARα, inflammation and oxidative stress. Increased FGF23 serum levels are correlated to inflammatory, renal and cardiovascular diseases, thus FGF23 represents an important therapeutic target and disease marker. Investigations unveiling regulation of FGF23 expression and synthesis as well as underlying mechanisms are therefore of high clinical significance. Hence, the present work aimed to elucidate a relevance of impaired metabolism on FGF23 formation, therefore establishing a basis for improved diagnosis as well as therapeutic approaches reducing morbidity and mortality in lactic acidosis, diabetic ketoacidosis or hyperhomocysteinemia. To this end, regulation of FGF23 synthesis under the influence of lactate, ketone bodies and homocysteine was analyzed. Lactic acid and sodium lactate enhanced Fgf23 expression in UMR106 osteoblast-like cells, an effect translated into higher cFGF23 concentration in cell culture supernatants. Application of NFκB inhibitors wogonin and withaferin A demonstrated an NFκB-mediated up-regulation of Fgf23 expression through lactic acid. Despite the knowledge that NFκB is an inducer of FGF23 formation and lactate stimulates NFκB activity, this study is the first to reveal a direct regulation of lactate on FGF23 production. As lactic acidosis is a common comorbidity in diabetes mellitus type 2 or cancer and increased lactate serum concentrations are associated with higher mortality, the findings of this study demonstrate FGF23 to be another useful biomarker for disease monitoring and prognosis. Furthermore homocysteine is a new regulator of FGF23 synthesis as shown within the present work, thus increasing Fgf23 expression and cFGF23 abundance in UMR106 cells. This effect is mediated by enhanced oxidative stress which stimulates FGF23 production, and is abolished by application of anti-oxidative ascorbic acid. Homocysteine serum levels are associated with versatile pathologies and its link to FGF23 signaling is therefore of clinical relevance, particularly in cardiovascular and renal diseases. In another investigation as part of this work, the ketone body βHB was identified as stimulator of FGF23 synthesis in UMR106 osteoblast-like cells as well as in primary cardiomyocytes, NRVM. Within NRVM, regulation of Fgf23 expression was shown to be dependent on MCT1/2 and HCAR2. Furthermore, intracellular activation of NFκB by βHB impacting on FGF23 synthesis was demonstrated in UMR106 cells. Moreover, short-term fasting (16 h) or βHB sodium salt administration increased FGF23 serum concentrations in C57BL/6 mice. These effects are of high relevance, since fasting-induced FGF23 synthesis was associated with lower NaPi-IIa and αklotho expression as well as with higher Cyp24a1 expression. In line with high FGF23 levels and enhanced Cyp24a1 expression, calcitriol serum levels of fasted animals were significantly lower compared to mice fed ad libitum. Other serum parameters including phosphate, calcium and PTH did not differ between both study groups. Further investigations revealed an important role of the heart as well as of thymus, spleen and pancreas in fasting-induced FGF23 synthesis. However, Fgf23 expression in bone and bone marrow did not differ between fasted mice and mice fed ad libitum, and was not detectable in liver tissue. As fasting and ketone body production are thought to be beneficial for various diseases and longevity, the findings of this investigation have enormous clinical implications. Since FGF23 has been demonstrated to be an important disease marker, and fasting induces FGF23 synthesis, blood samples of patients in fasting states may require careful interpretation. In conclusion, the present work is the first to demonstrate a direct regulation of FGF23 synthesis through lactate, ketone bodies and homocysteine. Hereby, NFκB signaling and generation of oxidative stress play a pivotal role. As FGF23 formation has been shown to be regulated through short-term fasting and to impact on phosphate homeostasis within the present work, the findings are highly implicated in physiology and pathophysiology. With respect to development of cardiovascular or renal diseases through lactic acidosis, diabetic ketoacidosis and homocysteinemia as well as to the relevance of FGF23 in these pathologies, the results of the present work are of significance for improved disease monitoring and establishment of new therapeutic approaches. Future investigations examining an involvement of metabolic regulators, e.g. insulin, mTOR, AMPK, PPARα, or of FGF co-receptor αklotho may provide further promising targets for therapy, diagnosis and prognosis of metabolic diseases.

Browse

Browsing Institut für Biologie by Person "Alber, Jana"