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DOI: 10.1055/a-2237-8863
Bilirubin Down-Regulates Oxidative Stress and Fibroblast Growth Factor 23 Expression in UMR106 Osteoblast-Like Cells
Funding Information Deutsche Forschungsgemeinschaft — http://dx.doi.org/10.13039/501100001659; Fo695/2–1Abstract
Introduction Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate and vitamin D metabolism in the kidney, and its higher levels in plasma are associated with poorer outcomes in kidney and cardiovascular diseases. It is produced by bone cells upon enhanced oxidative stress and inhibits renal phosphate reabsorption and calcitriol (active form of vitamin D) production. Bilirubin, the final product of the heme catabolic pathway in the vascular bed, has versatile biological functions, including antioxidant and anti-inflammatory effects. This study explored whether bilirubin alters FGF23 production.
Methods Experiments were performed using UMR106 osteoblast-like cells. Fgf23 transcript levels were determined by quantitative real-time polymerase chain reaction, C-terminal and intact FGF23 protein levels were determined by enzyme-linked immunosorbent assay, and cellular oxidative stress was assessed by CellROX assay.
Results Unconjugated bilirubin down-regulated Fgf23 gene transcription and FGF23 protein abundance; these effects were paralleled by lower cellular oxidative stress levels. Also, conjugated bilirubin reduced Fgf23 mRNA abundance.
Conclusion Bilirubin down-regulates FGF23 production in UMR106 cells, an effect likely to be dependent on the reduction of cellular oxidative stress.
Publication History
Received: 07 June 2023
Received: 14 December 2023
Accepted: 18 December 2023
Article published online:
19 February 2024
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References
- 1 Bilha SC, Bilha A, Ungureanu M-C. et al. FGF23 beyond the kidney: A new bone mass regulator in the general population. Horm Metab Res 2020; 52: 298-304 DOI: 10.1055/a-1151-2342.
- 2 Yuan D, Li J, Guo M. et al. Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment. PLoS One 2023; 18: e0280378 DOI: 10.1371/journal.pone.0280378.
- 3 Ogunmoroti O, Osibogun O, Zhao D. et al. Associations between endogenous sex hormones and FGF-23 among women and men in the Multi-Ethnic Study of Atherosclerosis. PLoS One 2022; 17: e0268759 DOI: 10.1371/journal.pone.0268759.
- 4 Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 2010; 61: 91-104 DOI: 10.1146/annurev.med.051308.111339.
- 5 Gattineni J, Bates C, Twombley K. et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297: F282-F291 DOI: 10.1152/ajprenal.90742.2008.
- 6 Baum M, Schiavi S, Dwarakanath V. et al. Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules. Kidney Int 2005; 68: 1148-1153 DOI: 10.1111/j.1523-1755.2005.00506.x.
- 7 Shimada T, Hasegawa H, Yamazaki Y. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19: 429-435 DOI: 10.1359/JBMR.0301264.
- 8 Lu Y, Feng JQ. FGF23 in skeletal modeling and remodeling. Curr Osteoporos Rep 2011; 9: 103-108 DOI: 10.1007/s11914-011-0053-4.
- 9 Xiao Z, Huang J, Cao L. et al. Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS One 2014; 9: e104154 DOI: 10.1371/journal.pone.0104154.
- 10 Leifheit-Nestler M, Große Siemer R, Flasbart K. et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol Dial Transplant 2016; 31: 1088-1099 DOI: 10.1093/ndt/gfv421.
- 11 Radhakrishnan K, Kim Y-H, Jung YS. et al. Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury. Proc Natl Acad Sci U S A 2021; 118: e2022841118 DOI: 10.1073/pnas.2022841118.
- 12 Prié D, Forand A, Francoz C. et al. Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PLoS One 2013; 8: e66182 DOI: 10.1371/journal.pone.0066182.
- 13 Smith ER, Tan S-J, Holt SG. et al. FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts. Sci Rep 2017; 7: 3345 DOI: 10.1038/s41598-017-02709-w.
- 14 Quarles LD. Fibroblast growth factor 23 and α-Klotho co-dependent and independent functions. Curr Opin Nephrol Hypertens 2019; 28: 16-25 DOI: 10.1097/MNH.0000000000000467.
- 15 Kuro-O M. The FGF23 and Klotho system beyond mineral metabolism. Clin Exp Nephrol 2017; 21: 64-69 DOI: 10.1007/s10157-016-1357-6.
- 16 Kuro-O M. A potential link between phosphate and aging—lessons from Klotho-deficient mice. Mech Ageing Dev 2010; 131: 270-275 DOI: 10.1016/j.mad.2010.02.008.
- 17 Chen C-D, Sloane JA, Li H. et al. The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 2013; 33: 1927-1939 DOI: 10.1523/JNEUROSCI.2080-12.2013.
- 18 Xie J, Cha S-K, An S-W. et al. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 2012; 3: 1238 DOI: 10.1038/ncomms2240.
- 19 Maltese G, Karalliedde J. The putative role of the antiageing protein klotho in cardiovascular and renal disease. Int J Hypertens 2012; 2012: 757469 DOI: 10.1155/2012/757469.
- 20 Fliser D, Kollerits B, Neyer U. et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: The Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007; 18: 2600-2608 DOI: 10.1681/ASN.2006080936.
- 21 Cornelissen A, Florescu R, Kneizeh K. et al. Fibroblast growth factor 23 and outcome prediction in patients with acute myocardial infarction. J Clin Med 2022; 11 DOI: 10.3390/jcm11030601.
- 22 Plischke M, Neuhold S, Adlbrecht C. et al. Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure. Eur J Clin Invest 2012; 42: 649-656 DOI: 10.1111/j.1365-2362.2011.02631.x.
- 23 Takashi Y, Maeda Y, Toyokawa K. et al. Fibroblast growth factor 23 and kidney function in patients with type 1 diabetes. PLoS One 2022; 17: e0274182 DOI: 10.1371/journal.pone.0274182.
- 24 Chu C, Elitok S, Zeng S. et al. C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival. BMC Nephrol 2021; 22: 125 DOI: 10.1186/s12882-021-02329-7.
- 25 Hocher C-F, Chen X, Zuo J. et al. Fibroblast growth factor 23 is associated with the development of gestational diabetes mellitus. Diabetes Metab Res Rev 2023; 39: e3704 DOI: 10.1002/dmrr.3704.
- 26 Flamme I, Ellinghaus P, Urrego D. et al. FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. PLoS One 2017; 12: e0186979 DOI: 10.1371/journal.pone.0186979.
- 27 Bär L, Feger M, Fajol A. et al. Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Proc Natl Acad Sci USA 2018; 115: 5804-5809 DOI: 10.1073/pnas.1800160115.
- 28 Glosse P, Fajol A, Hirche F. et al. A high-fat diet stimulates fibroblast growth factor 23 formation in mice through TNFα upregulation. Nutr Diabetes 2018; 8: 36 DOI: 10.1038/s41387-018-0037-x.
- 29 Yamazaki M, Kawai M, Miyagawa K. et al. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. J Bone Miner Metab 2015; 33: 342-354 DOI: 10.1007/s00774-014-0598-2.
- 30 Durlacher-Betzer K, Hassan A, Levi R. et al. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int 2018; 94: 315-325 DOI: 10.1016/j.kint.2018.02.026.
- 31 Voelkl J, Egli-Spichtig D, Alesutan I. et al. Inflammation: A putative link between phosphate metabolism and cardiovascular disease. Clin Sci (Lond) 2021; 135: 201-227 DOI: 10.1042/CS20190895.
- 32 Richter M, Schneider A, Maringanti R. et al. Transforming growth-factor-β is a potent inhibitor of FGF23 secretion from oncostatin M stimulated cardiomyocytes. Thorac Cardiovasc Surg 2016; 64(S 01): OP186 DOI: 10.1055/s-0036-1571618.
- 33 Hori M, Kinoshita Y, Taguchi M. et al. Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells. J Bone Miner Metab 2016; 34: 132-139 DOI: 10.1007/s00774-015-0651-9.
- 34 Hanudel MR, Chua K, Rappaport M. et al. Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice. Am J Physiol Renal Physiol 2016; 311: F1369-F1377 DOI: 10.1152/ajprenal.00281.2016.
- 35 Rausch S, Barholz M, Föller M. et al. Vitamin A regulates fibroblast growth factor 23 (FGF23). Nutrition 2020; 79-80: 110988 DOI: 10.1016/j.nut.2020.110988.
- 36 Glosse P, Feger M, Mutig K. et al. AMP-activated kinase is a regulator of fibroblast growth factor 23 production. Kidney Int 2018; 94: 491-501 DOI: 10.1016/j.kint.2018.03.006.
- 37 Vidal A, Rios R, Pineda C. et al. Direct regulation of fibroblast growth factor 23 by energy intake through mTOR. Sci Rep 2020; 10: 1795 DOI: 10.1038/s41598-020-58663-7.
- 38 Bär L, Hase P, Föller M. PKC regulates the production of fibroblast growth factor 23 (FGF23). PLoS One 2019; 14: e0211309 DOI: 10.1371/journal.pone.0211309.
- 39 Sullivan JI, Rockey DC. Diagnosis and evaluation of hyperbilirubinemia. Curr Opin Gastroenterol 2017; 33: 164-170 DOI: 10.1097/MOG.0000000000000354.
- 40 Vítek L. Bilirubin as a signaling molecule. Med Res Rev 2020; 40: 1335-1351 DOI: 10.1002/med.21660.
- 41 Vítek L, Ostrow JD. Bilirubin chemistry and metabolism; harmful and protective aspects. Curr Pharm Des 2009; 15: 2869-2883 DOI: 10.2174/138161209789058237.
- 42 Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician 2004; 69: 299-304
- 43 Bulmer AC, Verkade HJ, Wagner K-H. Bilirubin and beyond: A review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res 2013; 52: 193-205 DOI: 10.1016/j.plipres.2012.11.001.
- 44 Ihara H, Hashizume N, Shimizu N. et al. Threshold concentration of unbound bilirubin to induce neurological deficits in a patient with type I Crigler-Najjar syndrome. Ann Clin Biochem 1999; 36: 347-352 DOI: 10.1177/000456329903600307.
- 45 Ehlers L, Netz LAW, Reiner J. et al. Effects of bile duct ligation and ghrelin treatment on the colonic barrier and microbiome of mice. Pharmacology 2022; 107: 564-573 DOI: 10.1159/000527142.
- 46 Vítek L. Bilirubin and atherosclerotic diseases. Physiol Res 2017; 66: S11-S20 DOI: 10.33549/physiolres.933581.
- 47 Bosma PJ, Chowdhury JR, Bakker C. et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171-1175 DOI: 10.1056/NEJM199511023331802.
- 48 Vítek L. Bilirubin as a predictor of diseases of civilization. Is it time to establish decision limits for serum bilirubin concentrations?. Arch Biochem Biophys 2019; 672: 108062 DOI: 10.1016/j.abb.2019.108062.
- 49 Ziberna L, Martelanc M, Franko M. et al. Bilirubin is an endogenous antioxidant in human vascular endothelial cells. Sci Rep 2016; 6: 29240 DOI: 10.1038/srep29240.
- 50 Vitek L, Hinds TD, Stec DE. et al. The physiology of bilirubin: Health and disease equilibrium. Trends Mol Med 2023; DOI: 10.1016/j.molmed.2023.01.007.
- 51 Vítek L, Tiribelli C. Bilirubin: The yellow hormone?. J Hepatol 2021; 75: 1485-1490 DOI: 10.1016/j.jhep.2021.06.010.
- 52 Domazetovic V, Falsetti I, Ciuffi S. et al. Effect of oxidative stress-induced apoptosis on active FGF23 levels in MLO-Y4 cells: The protective role of 17-β-estradiol. Int J Mol Sci 2022; 23: 2103 DOI: 10.3390/ijms23042103.
- 53 Lang F, Leibrock C, Pandyra AA. et al. Phosphate homeostasis, inflammation and the regulation of FGF-23. Kidney Blood Press Res 2018; 43: 1742-1748 DOI: 10.1159/000495393.
- 54 Stec DE, John K, Trabbic CJ. et al. Bilirubin binding to PPARα inhibits lipid accumulation. PLoS One 2016; 11: e0153427 DOI: 10.1371/journal.pone.0153427.
- 55 Ewendt F, Hirche F, Feger M. et al. Peroxisome proliferator-activated receptor α (PPARα)-dependent regulation of fibroblast growth factor 23 (FGF23). Pflügers Archiv 2020; 472: 503-511 DOI: 10.1007/s00424-020-02363-8.
- 56 DiNicolantonio JJ, McCarty MF, O’Keefe JH. Antioxidant bilirubin works in multiple ways to reduce risk for obesity and its health complications. Open Heart 2018; 5: e000914 DOI: 10.1136/openhrt-2018-000914.
- 57 Maruhashi T, Soga J, Fujimura N. et al. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation 2012; 126: 598-603 DOI: 10.1161/CIRCULATIONAHA.112.105775.
- 58 Hana CA, Klebermass E-M, Balber T. et al. Inhibition of lipid accumulation in skeletal muscle and liver cells: A protective mechanism of bilirubin against diabetes mellitus type 2. Front Pharmacol 2020; 11: 636533 DOI: 10.3389/fphar.2020.636533.
- 59 Wallner M, Marculescu R, Doberer D. et al. Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert’s syndrome. Clin Sci (Lond) 2013; 125: 257-264 DOI: 10.1042/CS20120661.
- 60 Faul C, Amaral AP, Oskouei B. et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121: 4393-4408 DOI: 10.1172/JCI46122.
- 61 Lee Y, Kim H, Kang S. et al. Bilirubin nanoparticles as a nanomedicine for anti-inflammation therapy. Angew Chem Int Ed Engl 2016; 55: 7460-7463 DOI: 10.1002/anie.201602525.
- 62 Roy-Chowdhury N, Wang X, Roy-Chowdhury J. Bile Pigment Metabolism and Its Disorders. In: Emery and Rimoin’s principles and practice of medical genetics and genomics. Elsevier; 2020: 507-553 DOI: 10.1016/B978-0-12-812532-8.00019-7
- 63 Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem 2007; 43: 1-57 DOI: 10.1016/s0065-2423(06)43001-8.
- 64 Vogel ME, Zucker SD. Bilirubin acts as an endogenous regulator of inflammation by disrupting adhesion molecule-mediated leukocyte migration. Inflamm Cell Signal 2016; 3: e1178 DOI: 10.14800/ics.1178.
- 65 Francis C, David V. Inflammation regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens 2016; 25: 325-332 DOI: 10.1097/MNH.0000000000000232.
- 66 Huang J, Zhao Q, Li J. et al. Correlation between neonatal hyperbilirubinemia and vitamin D levels: A meta-analysis. PLoS One 2021; 16: e0251584 DOI: 10.1371/journal.pone.0251584.
- 67 van der Veere CN, Schoemaker B, Bakker C. et al. Influence of dietary calcium phosphate on the disposition of bilirubin in rats with unconjugated hyperbilirubinemia. Hepatology 1996; 24: 620-626 DOI: 10.1002/hep.510240326.