title: Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli.
abstract: Fibroblast growth factor-23 (FGF23), produced by osteocytes, is the key physiological regulator of phosphate homeostasis. Sepsis patients often experience transient hypophosphataemia, suggesting the regulation of FGF23 levels by pro-inflammatory factors. Here, we used the osteocyte-like cell line IDG-SW3 to investigate the effect of pro-inflammatory stimuli on FGF23 production. In differentiated IDG-SW3 cultures, basal Fgf23 mRNA was dose-dependently up-regulated by pro-inflammatory cytokines TNF, IL-1β and TWEAK, and bacterial LPS. Similar effects were observed in human bone samples. TNF- and IL-1β-induced Fgf23 expression was NF-κB-dependent. Conversely, mRNA encoding negative regulators of FGF23, Phex, Dmp1 and Enpp1, were suppressed by TNF, IL-1β, TWEAK and LPS, independent of NF-κβ signalling. Galnt3, the protein product of which protects intact FGF23 protein from furin/furin-like proprotein convertase cleavage, increased in response to these treatments. C-terminal FGF23 and intact FGF23 protein levels also increased, the latter only in the presence of Furin inhibitors, suggesting that enzymatic cleavage exerts critical control of active FGF23 secretion by osteocytes. Our results demonstrate in principle that pro-inflammatory stimuli are capable of increasing osteocyte secretion of FGF23, which may contribute to hypophosphataemia during sepsis and possibly other inflammatory conditions.
authors.affiliation: Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ito
authors.affiliation: Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Asiri R
authors.initials: AR
authors.lastname: Wijenayaka
authors.affiliation: Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Prideaux
authors.affiliation: Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kogawa
authors.affiliation: Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Renee T
authors.initials: RT
authors.lastname: Ormsby
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, The University of Adelaide, Woodville, SA 5011, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
authors.affiliation: Department of Oral Biology, University of Missouri-Kansas City School of Dentistry, Kansas, MO 64108, United States.
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Bonewald
authors.affiliation: Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.affiliation: Bone Cell Biology Group, Centre for Orthopaedic & Trauma Research, The University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: gerald.atkins@adelaide.edu.au.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
mesh_terms: D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D000074049:Cytokine TWEAK; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D048069:Tumor Necrosis Factors / Q000633:toxicity
chemical_list: D000074049:Cytokine TWEAK; C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010750:Phosphoproteins; C439524:TNF protein, human; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; D011755:Pyrophosphatases
keywords: FGF23; IL-1; LPS; Pro-inflammatory cytokines; TNF; TWEAK