nach oben

Erschienen in:

01.04.2013 | Original Research

1,25-Dihydroxyvitamin D₃ Regulation of Fibroblast Growth Factor-23 Expression in Bone Cells: Evidence for Primary and Secondary Mechanisms Modulated by Leptin and Interleukin-6

verfasst von: Rimpi K. Saini, Ichiro Kaneko, Peter W. Jurutka, Ryan Forster, Antony Hsieh, Jui-Cheng Hsieh, Mark R. Haussler, G. Kerr Whitfield

Erschienen in: Calcified Tissue International | Ausgabe 4/2013

Einloggen, um Zugang zu erhalten

Abstract

Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption and to prevent hypervitaminosis D by feedback repressing 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is induced by the nuclear vitamin D receptor (VDR) bound to 1,25(OH)₂D₃, but cycloheximide sensitivity of this induction suggests that it may occur largely via secondary mechanisms requiring cooperating transcription factors. We therefore sought to identify 1,25(OH)₂D₃-regulated transcription factors that might impact FGF23 expression. Although neither leptin nor interleukin-6 (IL-6) alone affects FGF23 expression, leptin treatment was found to potentiate 1,25(OH)₂D₃ upregulation of FGF23 in UMR-106 cells, whereas IL-6 treatment blunted this upregulation. Genomic analyses revealed conserved binding sites for STATs (signal transduction mediators of leptin and IL-6 action) along with transcription factor ETS1 in human and other mammalian FGF23 genes. Further, STAT3, STAT1, ETS1, and VDR mRNAs were induced in a dose-dependent manner by 1,25(OH)₂D₃ in UMR-106 cells. Bioinformatic analysis identified nine potential VDREs in a genomic interval containing human FGF23. Six of the putative VDREs were capable of mediating direct transcriptional activation of a heterologous reporter gene when bound by a 1,25(OH)₂D₃-liganded VDR complex. A model is proposed wherein 1,25(OH)₂D₃ upregulates FGF23 production directly via multiple VDREs and indirectly via induction of STAT3, ETS1, and VDR transcription factors that are then activated via cell surface and intracellular signaling to cooperate in the induction of FGF23 through DNA looping and generation of euchromatin architecture.

Haussler MR, Haussler CA, Whitfield GK, Hsieh JC, Thompson PD, Barthel TK et al (2010) The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the “Fountain of Youth” to mediate healthful aging. J Steroid Biochem Mol Biol 121:88–97PubMedCrossRef

Haussler MR, Whitfield GK, Haussler CA, Hsieh J-C, Jurutka PW (2011) Nuclear vitamin D receptor: natural ligands, molecular structure–function, and transcriptional control of vital genes. In: Feldman D, Pike JW, Adams JS (eds) vitamin D, vol 1, 3rd edn. Academic Press, Amsterdam, pp 137–170CrossRef

Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T, Kato S (1998) The promoter of the human 25-hydroxyvitamin D₃ 1 alpha-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1 alpha,25(OH)₂D₃. Biochem Biophys Res Commun 249:11–16PubMedCrossRef

Haussler MR, Whitfield GK, Haussler CA, Hsieh J-C, Thompson PD, Selznick SH et al (1998) The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 13:325–349PubMedCrossRef

Kuro-o M (2010) Overview of the FGF23–Klotho axis. Pediatr Nephrol 25:583–590PubMedCrossRef

Razzaque MS (2009) The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 5:611–619PubMedCrossRef

Kolek OI, Hines ER, Jones MD, Lesueur LK, Lipko MA, Kiela PR et al (2005) 1α25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal–gastrointestinal–skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289:G1036–G1042PubMedCrossRef

Saji F, Shigematsu T, Sakaguchi T, Ohya M, Orita H, Maeda Y et al (2010) Fibroblast growth factor 23 production in bone is directly regulated by 1α25-dihydroxyvitamin D, but not PTH. Am J Physiol Renal Physiol 299:F1212–F1217PubMedCrossRef

Farrow EG, Davis SI, Summers LJ, White KE (2009) Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 20:955–960PubMedCrossRef

10.

Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, Nakatani T et al (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23–FGFR–Klotho complex formation. Proc Natl Acad Sci USA 107:407–412PubMedCrossRef

11.

Quarles LD (2008) Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118:3820–3828PubMedCrossRef

12.

Yu X, Sabbagh Y, Davis SI, Demay MB, White KE (2005) Genetic dissection of phosphate-and vitamin D–mediated regulation of circulating Fgf23 concentrations. Bone 36:971–977PubMedCrossRef

13.

Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y et al (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435PubMedCrossRef

14.

Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T et al (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568PubMed

15.

Gutierrez OM (2011) Increased serum phosphate and adverse clinical outcomes: unraveling mechanisms of disease. Curr Opin Nephrol Hypertens 20:224–228PubMedCrossRef

16.

Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A et al (2007) Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the mild to moderate kidney disease (MMKD) study. J Am Soc Nephrol 18:2600–2608PubMedCrossRef

17.

Alizadeh Naderi AS, Reilly RF (2010) Hereditary disorders of renal phosphate wasting. Nat Rev Nephrol 6:657–665PubMedCrossRef

18.

Krejci P, Prochazkova J, Bryja V, Kozubik A, Wilcox WR (2009) Molecular pathology of the fibroblast growth factor family. Hum Mutat 30:1245–1255PubMedCrossRef

19.

Chong WH, Molinolo AA, Chen CC, Collins MT (2011) Tumor-induced osteomalacia. Endocr Relat Cancer 18:R53–R77PubMedCrossRef

20.

Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K (2009) Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res 19:24–32PubMedCrossRef

21.

Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM et al (2002) The human genome browser at UCSC. Genome Res 12:996–1006PubMed

22.

Haussler MR, Haussler CA, Bartik L, Whitfield GK, Hsieh JC, Slater S et al (2008) Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev 66:S98–S112PubMedCrossRef

23.

Hsieh J-C, Jurutka PW, Galligan MA, Terpening CM, Haussler CA, Samuels DS et al (1991) Human vitamin D receptor is selectively phosphorylated by protein kinase C on serine 51, a residue crucial to its trans-activation function. Proc Natl Acad Sci USA 88:9315–9319PubMedCrossRef

24.

Hsieh J-C, Jurutka PW, Nakajima S, Galligan MA, Haussler CA, Shimizu Y et al (1993) Phosphorylation of the human vitamin D receptor by protein kinase C: biochemical and functional evaluation of the serine 51 recognition site. J Biol Chem 268:15118–15126PubMed

25.

MacDonald PN, Dowd DR, Nakajima S, Galligan MA, Reeder MC, Haussler CA et al (1993) Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D₃–activated expression of the rat osteocalcin gene. Mol Cell Biol 13:5907–5917PubMed

26.

Terpening CM, Haussler CA, Jurutka PW, Galligan MA, Komm BS, Haussler MR (1991) The vitamin D–responsive element in the rat bone gla protein is an imperfect direct repeat that cooperates with other cis-elements in 1,25-dihydroxyvitamin D₃–mediated transcriptional activation. Mol Endocrinol 5:373–385PubMedCrossRef

27.

Thompson PD, Jurutka PW, Whitfield GK, Myskowski SM, Eichhorst KR, Dominguez CE et al (2002) Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochem Biophys Res Commun 299:730–738PubMedCrossRef

28.

Dreszer TR, Karolchik D, Zweig AS, Hinrichs AS, Raney BJ, Kuhn RM et al (2012) The UCSC Genome Browser database: extensions and updates 2011. Nucleic Acids Res 40:D918–D923PubMedCrossRef

29.

Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M et al (2006) Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17:1305–1315PubMedCrossRef

30.

Tsuji K, Maeda T, Kawane T, Matsunuma A, Horiuchi N (2010) Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D₃ synthesis in leptin-deficient mice. J Bone Miner Res 25:1711–1723PubMedCrossRef

31.

Mendoza JM, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH et al (2012) Fibroblast growth factor 23 and inflammation in CKD. Clin J Am Soc Nephrol 7:1155–1162CrossRef

32.

Liu WH, Zhou QL, Ao X, Yu HL, Peng WS, He N (2012) Fibroblast growth factor-23 and interleukin-6 are risk factors for left ventricular hypertrophy in peritoneal dialysis patients. J Cardiovasc Med (Hagerstown) 13:565–569CrossRef

33.

Haussler MR, Whitfield GK, Kaneko I, Forster R, Saini R, Hsieh JC et al (2012) The role of vitamin D in the FGF23, klotho, and phosphate bone–kidney endocrine axis. Rev Endocr Metab Disord 13:57–69PubMedCrossRef

34.

Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T et al (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4:651–657PubMedCrossRef

35.

Euskirchen GM, Rozowsky JS, Wei CL, Lee WH, Zhang ZD, Hartman S et al (2007) Mapping of transcription factor binding regions in mammalian cells by ChIP: comparison of array-and sequencing-based technologies. Genome Res 17:898–909PubMedCrossRef

36.

Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M et al (2010) Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J 29:2147–2160PubMedCrossRef

37.

Blanchette M, Kent WJ, Riemer C, Elnitski L, Smit AF, Roskin KM et al (2004) Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res 14:708–715PubMedCrossRef

38.

Meyer MB, Lee CH, Benkuskey NA, Sen B, Rubin J, Pike JW (2012) VDR inhibits mouse mesenchymal stem cell osteogenic differentiation and mineralization. In: Abstracts from the 15th Workshop on Vitamin D, Houston, TX, June 20–22, p 27

39.

Meyer MB, Goetsch PD, Pike JW (2010) Genome-wide analysis of the VDR/RXR cistrome in osteoblast cells provides new mechanistic insight into the actions of the vitamin D hormone. J Steroid Biochem Mol Biol 121:136–141PubMedCrossRef

40.

Pike JW, Meyer MB (2011) Regulation of mouse Cyp24a1 expression via promoter-proximal and downstream-distal enhancers highlights new concepts of 1,25-dihydroxyvitamin D₃ action. Arch Biochem Biophys 523:2–8PubMedCrossRef

41.

Ito M, Sakai Y, Furumoto M, Segawa H, Haito S, Yamanaka S et al (2005) Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells. Am J Physiol Endocrinol Metab 288:E1101–E1109PubMedCrossRef

42.

Kim S, Yamazaki M, Zella LA, Shevde NK, Pike JW (2006) Activation of receptor activator of NF-kappaB ligand gene expression by 1,25-dihydroxyvitamin D₃ is mediated through multiple long-range enhancers. Mol Cell Biol 26:6469–6486PubMedCrossRef

43.

Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE et al (2011) Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 49:636–643PubMedCrossRef

44.

Fu Q, Manolagas SC, O’Brien CA (2006) Parathyroid hormone controls receptor activator of NF-kappaB ligand gene expression via a distant transcriptional enhancer. Mol Cell Biol 26:6453–6468PubMedCrossRef

45.

Vidal M, Ramana CV, Dusso AS (2002) Stat1–vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. Mol Cell Biol 22:2287–2777CrossRef

46.

Drane P, Compe E, Catez P, Chymkowitch P, Egly JM (2004) Selective regulation of vitamin D receptor–responsive genes by TFIIH. Mol Cell 16:187–197PubMedCrossRef

47.

Miedlich SU, Zhu ED, Sabbagh Y, Demay MB (2010) The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice. Endocrinology 151:4607–4612PubMedCrossRef

48.

Orfanidou T, Malizos KN, Varitimidis S, Tsezou A (2012) 1,25-Dihydroxyvitamin D₃ and extracellular inorganic phosphate activate mitogen-activated protein kinase pathway through fibroblast growth factor 23 contributing to hypertrophy and mineralization in osteoarthritic chondrocytes. Exp Biol Med (Maywood) 237:241–253CrossRef

49.

Martin A, Liu S, David V, Li H, Karydis A, Feng JQ et al (2011) Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25:2551–2562PubMedCrossRef

50.

Yamazaki M, Ozono K, Okada T, Tachikawa K, Kondou H, Ohata Y et al (2010) Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. J Cell Biochem 111:1210–1221PubMedCrossRef

Titel: 1,25-Dihydroxyvitamin D3 Regulation of Fibroblast Growth Factor-23 Expression in Bone Cells: Evidence for Primary and Secondary Mechanisms Modulated by Leptin and Interleukin-6
verfasst von: Rimpi K. Saini
Ichiro Kaneko
Peter W. Jurutka
Ryan Forster
Antony Hsieh
Jui-Cheng Hsieh
Mark R. Haussler
G. Kerr Whitfield
Publikationsdatum: 01.04.2013
Verlag: Springer-Verlag
Erschienen in: Calcified Tissue International / Ausgabe 4/2013
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-012-9683-5

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

RAS-Blocker bei Hyperkaliämie möglichst nicht sofort absetzen

14.05.2024 Hyperkaliämie Nachrichten

Bei ausgeprägter Nierenfunktionsstörung steigen unter der Einnahme von Renin-Angiotensin-System(RAS)-Hemmstoffen nicht selten die Serumkaliumspiegel. Was in diesem Fall zu tun ist, erklärte Prof. Jürgen Floege beim diesjährigen Allgemeinmedizin-Update-Seminar.

Gestationsdiabetes: In der zweiten Schwangerschaft folgenreicher als in der ersten

13.05.2024 Gestationsdiabetes Nachrichten

Das Risiko, nach einem Gestationsdiabetes einen Typ-2-Diabetes zu entwickeln, hängt nicht nur von der Zahl, sondern auch von der Reihenfolge der betroffenen Schwangerschaften ab.

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

13.05.2024 Pankreaskarzinom Nachrichten

Gerade bei aggressiven Malignomen wie dem duktalen Adenokarzinom des Pankreas könnte Früherkennung die Therapiechancen verbessern. Noch jedoch klafft hier eine Lücke. Ein Studienteam hat einen Weg gesucht, sie zu schließen.

Battle of Experts: Sport vs. Spritze bei Adipositas und Typ-2-Diabetes

11.05.2024 DDG-Jahrestagung 2024 Kongressbericht

Im Battle of Experts traten zwei Experten auf dem Diabeteskongress gegeneinander an: Die eine vertrat die Auffassung „Sport statt Spritze“ bei Adipositas und Typ-2-Diabetes, der andere forderte „Spritze statt Sport!“ Am Ende waren sie sich aber einig: Die Kombination aus beidem erzielt die besten Ergebnisse.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Bildnachweise

Die Leitlinien für Ärztinnen und Ärzte, Ärztin führt eine Nierenultraschalluntersuchung durch/© Graphicroyalty / stock.adobe.com (Symbolbild mit Fotomodell), Schwangere misst Blutzucker/© MMPhotography / Getty Images / iStock (Symbolbild mit Fotomodell), Duktales Pankreaskarzinom/© Dörffel, Y., Wermke, W. / all rights reserved Springer Medizin Verlag GmbH, Füße einer adipösen Frau auf einem Laufband/© Idanupong / stock.adobe.com (Symbolbild mit Fotomodell)

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2013

Identification of Gender-Specific Candidate Genes that Influence Bone Microarchitecture in Chromosome 1

Calcified Cartilage Islands in Rat Cortical Bone

The Influence of Therapeutic Radiation on the Patterns of Bone Remodeling in Ovary-Intact and Ovariectomized Mice

Antiretroviral Therapy and Pregnancy: Effect on Cortical Bone Status of Human Immunodeficiency Virus–Infected Caucasian Women as Assessed by Quantitative Ultrasonography

Acute Effects of Glucocorticoids on Serum Markers of Osteoclasts, Osteoblasts, and Osteocytes