title: NFκB-sensitive Orai1 expression in the regulation of FGF23 release.
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 Ca(2+) channel accomplishing store-operated Ca(2+) 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 Ca(2+) activity utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, UMR106 and IPO cells expressed Ca(2+) 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 Ca(2+) 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 Ca(2+) entry.
  
  
  
  Osteoblast UMR106 and IPO cells express Ca(2+) channel Orai1. Osteoblast store-operated Ca(2+) entry is accomplished by NFκB-sensitive Orai1. Osteoblast Fgf23 transcription is upregulated by increase in the cytosolic Ca(2+) activity. Fgf23 transcription is decreased by Orai inhibitors and Orai1 silencing. Fgf23 transcription is lowered by NFκB inhibitors.
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Anja T
authors.initials: AT
authors.lastname: Umbach
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Hajar
authors.initials: H
authors.lastname: Fakhri
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Abul
authors.initials: A
authors.lastname: Fajol
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Madhuri S
authors.initials: MS
authors.lastname: Salker
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital of Tübingen, Osianderstr. 2-8, 72076, Tübingen, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Alexander
authors.affiliation: Institute of Physiology and NCCR Kidney. CH, University of Zürich, Winterthurerstr. 190, CH-8057, Zürich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Spichtig
authors.affiliation: Institute of Physiology and NCCR Kidney. CH, University of Zürich, Winterthurerstr. 190, CH-8057, Zürich, Switzerland.
authors.forename: Arezoo
authors.initials: A
authors.lastname: Daryadel
authors.affiliation: Institute of Physiology and NCCR Kidney. CH, University of Zürich, Winterthurerstr. 190, CH-8057, Zürich, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.affiliation: Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120, Halle (Saale), Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany. florian.lang@uni-tuebingen.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D042541:Intracellular Space / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D000071740:ORAI1 Protein / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism; D051381:Rats
chemical_list: C000717428:Fgf23 protein, mouse; D016328:NF-kappa B; D000071740:ORAI1 Protein; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002118:Calcium
keywords: 1,25(OH)2D3; Calcium; NFκB; Orai1; SOCE