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Journal of Molecular Medicine

, Volume 94, Issue 5, pp 557–566 | Cite as

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

  • Bingbing Zhang
  • Jing Yan
  • Anja T. Umbach
  • Hajar Fakhri
  • Abul Fajol
  • Sebastian Schmidt
  • Madhuri S. Salker
  • Hong Chen
  • Dorothea Alexander
  • Daniela Spichtig
  • Arezoo Daryadel
  • Carsten A. Wagner
  • Michael Föller
  • Florian LangEmail author
Original Article

Abstract

Fibroblast growth factor (FGF23) plasma levels are elevated in cardiac and renal failure and correlate with poor clinical prognosis of those disorders. Both disorders are associated with inflammation and activation of the inflammatory transcription factor NFκB. An excessive FGF23 level is further observed in Klotho-deficient mice. The present study explored a putative sensitivity of FGF23 expression to transcription factor NFκB, which is known to upregulate Orai1, the Ca2+ channel accomplishing store-operated Ca2+ entry (SOCE). In osteoblastic cells (UMR106) and immortalized primary periosteal (IPO) cells, protein abundance was determined by Western blotting, and in UMR106 cells, transcript levels were quantified by RT-PCR, cytosolic Ca2+ activity utilizing Fura-2-fluorescence, and SOCE from Ca2+ entry following store depletion by thapsigargin. As a result, UMR106 and IPO cells expressed Ca2+ channel Orai1. SOCE was lowered by NFκB inhibitor wogonin as well as by Orai1 inhibitors 2-APB and YM58483. UMR106 cell Fgf23 transcripts were increased by stimulation of SOCE and Ca2+ ionophore ionomycin and decreased by Orai inhibitors 2-APB, YM58483 and SK&F96365, by Orai1 silencing, as well as by NFκB inhibitors wogonin, withaferin A, and CAS 545380-34-5. In conclusion, Fgf23 expression is upregulated by stimulation of NFκB-sensitive, store-operated Ca2+ entry.

Key messages

  • Osteoblast UMR106 and IPO cells express Ca2+ channel Orai1.

  • Osteoblast store-operated Ca2+ entry is accomplished by NFκB-sensitive Orai1.

  • Osteoblast Fgf23 transcription is upregulated by increase in the cytosolic Ca2+ activity.

  • Fgf23 transcription is decreased by Orai inhibitors and Orai1 silencing.

  • Fgf23 transcription is lowered by NFκB inhibitors.

Keywords

1,25(OH)2D3 SOCE Calcium Orai1 NFκB 

Notes

Acknowledgments

The authors acknowledge the technical assistance of E. Faber. The study was supported by the Deutsche Forschungsgemeinschaft (La 315/15-1, Fo 695/1-1, and Fo 695/1-2) and the National Center for Competence in Research NCCR Kidney. CH was financed by the Swiss National Science Foundation.

Authors’ contribution

MF and FL made the study design. BZ, JY, ATU, HF, AF, SS, MSS, HC, DA, DS, and AD performed data collection. BZ, JY, SS, and CAW analyzed the data. MF, CAW, and FL interpreted the results. FL drafted the manuscript. FL wrote the manuscript. MF, CAW, and FL revised the manuscript content. BZ, JY, ATU, HF, AF, SS, MSS, HC, DA, DS, AD, CAW, MF, and FL read and approved the final version of the manuscript. FL takes responsibility for the integrity of the data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Bingbing Zhang
    • 1
  • Jing Yan
    • 1
  • Anja T. Umbach
    • 1
  • Hajar Fakhri
    • 1
  • Abul Fajol
    • 1
  • Sebastian Schmidt
    • 1
  • Madhuri S. Salker
    • 1
  • Hong Chen
    • 1
  • Dorothea Alexander
    • 2
  • Daniela Spichtig
    • 3
  • Arezoo Daryadel
    • 3
  • Carsten A. Wagner
    • 3
  • Michael Föller
    • 4
  • Florian Lang
    • 1
    Email author
  1. 1.Department of PhysiologyUniversity of TübingenTübingenGermany
  2. 2.Department of Oral and Maxillofacial SurgeryUniversity Hospital of TübingenTübingenGermany
  3. 3.Institute of Physiology and NCCR Kidney. CHUniversity of ZürichZürichSwitzerland
  4. 4.Institute of Agricultural and Nutritional SciencesMartin Luther University Halle-WittenbergHalle (Saale)Germany

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