Affinage

FGF23

Fibroblast growth factor 23 · UniProt Q9GZV9

Length
251 aa
Mass
28.0 kDa
Annotated
2026-06-09
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGF23 is a bone-derived endocrine hormone that controls systemic phosphate and vitamin D homeostasis and, at pathological concentrations, drives organ injury in chronic kidney disease (PMID:17086194, PMID:15998839). Canonical FGF23 signaling requires the co-receptor α-Klotho, which converts FGFR1c into a high-affinity FGF23 receptor; structurally, α-Klotho is a non-enzymatic scaffold that simultaneously tethers FGFR1c and the FGF23 C-terminal tail, with heparan sulfate required for receptor dimerization and activation (PMID:17086194, PMID:29342138). Through this Klotho-FGFR1c complex FGF23 activates RAS/RAF/MEK/ERK signaling to suppress renal NaPi-IIa and 1α-hydroxylase—independently of vitamin D/VDR signaling (PMID:15998839, PMID:20717920)—and acts on distal tubule to raise NCC membrane abundance via ERK1/2→SGK1→WNK4, causing Na+ retention, hypertension, and cardiac hypertrophy (PMID:24797667); it also acts directly on the parathyroid gland via Klotho-FGFR1 to suppress PTH through MAPK activation (PMID:20010546). In Klotho-independent settings, high FGF23 drives left ventricular hypertrophy by signaling through cardiac FGFR4 to activate PLCγ/calcineurin/NFAT, with FGFR4 blockade attenuating established LVH (PMID:21985788, PMID:28512310), and suppresses neutrophil recruitment by binding FGFR2 and activating PKA to inhibit Rap1-dependent β2 integrin activation, impairing innate immunity (PMID:26878171). FGF23 production by osteocytes is regulated by autocrine/paracrine FGFR1 signaling and by phosphate, PTH, aldosterone, and pro-inflammatory cytokines acting through NF-κB, ROS/MEK-ERK, and SGK1 pathways (PMID:25089825, PMID:25792238, PMID:26773502, PMID:25458698), while post-translational processing—FAM20C phosphorylation and furin cleavage versus GALNT3 O-glycosylation—determines the ratio of inactive fragments to secreted intact hormone (PMID:33338030). The furin-generated C-terminal fragment is itself bioactive, binding BMP2/BMP9 to block hepcidin induction and preserve iron availability during inflammation (PMID:37053547, PMID:32193252).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2006 High

    Established why FGF23 is tissue-selective despite ubiquitous FGFRs: α-Klotho is an obligate co-receptor that converts FGFR1c into a high-affinity FGF23 receptor.

    Evidence Renal binding assays, forced Klotho expression, and in vivo anti-Klotho antibody neutralization in mice

    PMID:17086194

    Open questions at the time
    • Did not resolve the atomic architecture of the ternary complex
    • Did not address Klotho-independent FGF23 actions
  2. 2018 High

    Resolved the structural basis of receptor assembly, showing α-Klotho is a non-enzymatic scaffold tethering both FGFR1c and the FGF23 C-terminal tail.

    Evidence X-ray crystallography of the 1:1:1 shed α-Klotho/FGFR1c/FGF23 ternary complex with functional validation

    PMID:29342138

    Open questions at the time
    • Heparan sulfate-bound dimeric activated state not crystallized
    • Structures of FGFR4 and FGFR2 complexes not defined
  3. 2005 High

    Showed FGF23 suppresses renal phosphate transport and 1α-hydroxylase through a VDR-independent mechanism, separating its effector actions from vitamin D signaling.

    Evidence Recombinant FGF23 administration to VDR-null mice with measurement of NaPi2a, 1α- and 24-hydroxylase mRNA

    PMID:15998839

    Open questions at the time
    • Did not define the renal intracellular signaling cascade
    • Dietary phosphate-stimulated FGF23 production was VDR-dependent, mechanism unresolved
  4. 2010 Medium

    Defined the canonical FGF23 intracellular cascade and linked it to phosphate sensing through a converging FGFR1 node.

    Evidence HEK293 transfection with proteolysis-resistant FGF23[R179Q], ERK1/2 and FRS2α phosphorylation, FGFR1 and PiT-1 knockdown

    PMID:20717920

    Open questions at the time
    • Cell line overexpression, not physiological target tissue
    • Did not require Klotho in this system
  5. 2011 High

    Identified a Klotho-independent pathological action of FGF23, demonstrating it directly causes cardiomyocyte hypertrophy via FGFR-dependent calcineurin-NFAT signaling.

    Evidence Isolated rat cardiomyocyte assays, intramyocardial/IV FGF23 injection, FGF-receptor blockade in a CKD model

    PMID:21985788

    Open questions at the time
    • Did not pinpoint which FGFR mediates the cardiac effect
    • Did not establish PLCγ upstream of calcineurin
  6. 2014 High

    Mapped the receptor and signaling specificity of FGF23-induced renal Na+ handling, connecting FGF23 to hypertension and volume expansion.

    Evidence Gain- and loss-of-function mouse models, NCC membrane western blots, chlorothiazide rescue

    PMID:24797667

    Open questions at the time
    • Did not reconcile the αKlotho-dependent renal effect with Klotho-independent cardiac effects
    • Long-term cardiovascular consequences not fully traced
  7. 2014 High

    Established autocrine/paracrine FGFR1 signaling within bone as a positive regulator of FGF23 production, identifying a feed-forward loop.

    Evidence Osteocyte-specific Fgfr1 conditional knockout, FGF23 promoter-luciferase assays, dominant-negative FGFR1 and pathway inhibitors

    PMID:25089825

    Open questions at the time
    • Upstream physiological ligand activating osteocyte FGFR1 not defined
    • Quantitative contribution relative to systemic regulators unclear
  8. 2014 Medium

    Linked inflammation to FGF23 production, showing cytokines and LPS induce Fgf23 via NF-κB while furin cleavage gates active hormone output.

    Evidence IDG-SW3 osteocyte stimulation and human bone, qRT-PCR/ELISA, NF-κB and furin inhibitors

    PMID:25458698

    Open questions at the time
    • Single-lab cell and tissue model
    • In vivo causal contribution of NF-κB not tested by genetic deletion
  9. 2015 Medium

    Refined how phosphate transcriptionally induces FGF23, implicating NADPH oxidase-derived ROS upstream of MEK-ERK.

    Evidence UMR-106 promoter-luciferase, ROS imaging, apocynin/PD98059/phosphonoformate inhibitors, mRNA stability assay

    PMID:25792238

    Open questions at the time
    • Cell culture only
    • Did not connect ROS pathway to FGFR1-mediated phosphate sensing
  10. 2016 Medium

    Identified aldosterone/mineralocorticoid receptor as a hormonal driver of FGF23, involving SGK1, NF-κB, and store-operated Ca2+ entry.

    Evidence UMR-106 culture, Fura-2 Ca2+ imaging, MR/SGK1/NF-κB/Ca2+-channel inhibitors, DOCA and salt depletion in mice

    PMID:26773502

    Open questions at the time
    • Single-lab mechanism
    • Tissue-specific genetic confirmation of MR-FGF23 axis lacking
  11. 2016 High

    Defined a Klotho-independent immunosuppressive action of FGF23, showing it impairs neutrophil recruitment through FGFR2/PKA/Rap1.

    Evidence Intravital microscopy, PMN adhesion assays, FGF23 neutralization in CKD mice, FGFR2 and PKA knockdown

    PMID:26878171

    Open questions at the time
    • Structural basis of FGF23-FGFR2 engagement not resolved
    • Relative clinical contribution to CKD infection risk not quantified
  12. 2017 High

    Identified FGFR4 as the specific cardiac receptor for FGF23-induced hypertrophy, providing a therapeutic target.

    Evidence FGFR4-specific blockade in 5/6 nephrectomy rats, FGFR4 knockout aging mice, in vitro cardiomyocyte assays

    PMID:28512310

    Open questions at the time
    • Did not fully delineate downstream effectors in this study
    • Whether contractility and hypertrophy share one pathway unresolved
  13. 2018 Medium

    Connected FGF23 cardiac signaling to nuclear Ca2+/CaMKII-HDAC4 and local angiotensin II, linking it to a hypertrophic gene program.

    Evidence NRVM Ca2+ imaging, cell area and hypertrophic gene readouts, losartan treatment, ATII peptide measurement

    PMID:30062428

    Open questions at the time
    • In vitro only
    • Causal role of local ATII in vivo not established
  14. 2019 Medium

    Extended the cardiac mechanism, implicating FGFR4-PLCγ/calcineurin/NFAT and local RAAS activation in hypertrophy and fibrosis.

    Evidence 5/6 nephrectomy rats and NRVM/NRCF cultures, losartan/spironolactone/cyclosporine A inhibition (and review synthesis)

    PMID:29892269 PMID:31540546

    Open questions at the time
    • Single-lab in vitro emphasis
    • Integration of RAAS, Ca2+, and NFAT into one circuit not fully resolved
  15. 2019 Medium

    Revealed a non-mineral CNS phenotype, showing FGF23 deficiency causes hippocampal-dependent cognitive impairment distinct from Klotho loss.

    Evidence Fgf23-deficient mice, hippocampal behavioral testing, neurogenesis and synaptic plasticity assays

    PMID:30911673

    Open questions at the time
    • Receptor and signaling pathway in brain unidentified
    • Cell-autonomous vs systemic mechanism unresolved
  16. 2020 High

    Identified a kidney-to-bone metabolite signal, glycerol-3-phosphate acting via LPA/LPAR1, that drives FGF23 production, especially in acute kidney injury.

    Evidence Human renal venous metabolomics, exogenous G-3-P in mice, GPAT inhibition, Lpar1 deletion, AKI models

    PMID:32065590

    Open questions at the time
    • Intracellular LPAR1-to-FGF23 transcription link not detailed
    • Relative importance versus phosphate/PTH regulation unclear
  17. 2021 High

    Defined a hepatic source of FGF23 in injury, showing IL-6-induced ERR-γ transcriptionally drives liver FGF23 during AKI.

    Evidence Folic acid AKI model, liver-specific ERRγ knockout, ERRγ overexpression, IL-6 neutralization, ERRγ inverse agonist

    PMID:33853949

    Open questions at the time
    • Functional consequence of hepatic vs bone FGF23 not separated
    • Whether hepatic FGF23 is intact or cleaved not defined here
  18. 2021 Medium

    Established a distinct bioactivity for the C-terminal FGF23 fragment in iron metabolism, alleviating inflammatory hypoferremia by lowering hepcidin.

    Evidence WT mouse LPS model, C-terminal FGF23 peptide administration, hepcidin and tissue/serum iron measurements

    PMID:32193252

    Open questions at the time
    • Molecular receptor/binding partner of the fragment not identified in this study
    • Single-lab pharmacological intervention
  19. 2021 Medium

    Consolidated the post-translational control of FGF23 output via FAM20C phosphorylation/furin cleavage versus GALNT3 O-glycosylation.

    Evidence Review synthesizing prior genetic and biochemical evidence

    PMID:33338030

    Open questions at the time
    • Review, not primary data
    • Relative in vivo flux through each branch not quantified
  20. 2023 High

    Provided direct molecular mechanism for C-terminal FGF23 bioactivity, showing it binds BMP2/BMP9 to block BMP-induced hepcidin and preserve iron during inflammation.

    Evidence Osteocyte-specific Fgf23 and Furin knockouts, Cter-FGF23 plus BMP2/BMP9 co-administration, Cter-Fgf23 overexpression, hepcidin/iron measurement

    PMID:37053547

    Open questions at the time
    • Structural basis of Cter-FGF23/BMP binding not resolved
    • Contribution in chronic vs acute inflammation not delineated
  21. 2024 High

    Extended hepatic FGF23 regulation to alcoholic liver disease through a CB1R-ERRγ-FGF23-CYP2E1 oxidative-stress axis.

    Evidence Hepatocyte-specific CB1R/ERRγ/FGF23 knockouts, chronic alcohol feeding, ERRγ inverse agonist, CYP2E1 and injury readouts

    PMID:38479224

    Open questions at the time
    • Receptor mediating FGF23-to-CYP2E1 effect not defined
    • Whether circulating vs autocrine hepatic FGF23 is responsible unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct receptor usage (FGFR1c/Klotho, FGFR4, FGFR2) and the intact-versus-C-terminal forms are integrated to produce tissue-specific physiological versus pathological outcomes remains unresolved.
  • No unified model of receptor/cofactor selection across tissues
  • Endogenous receptor for the C-terminal fragment's hepcidin effect not molecularly defined
  • Brain FGF23 signaling pathway unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 2
Partners
BMP2BMP9FGFR1FGFR2FGFR4FURINGALNT3KL
Complex memberships
FGF23–FGFR1c–α-Klotho ternary receptor complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Klotho binds FGF23 and converts FGFR1(IIIc) into a specific high-affinity FGF23 receptor; forced expression of Klotho enabled high-affinity FGF23 binding to cell surfaces and restored FGF23 responsiveness in a renal cell line. Injection of an anti-Klotho monoclonal antibody in wild-type mice induced FGF23 incompetence, establishing Klotho as an obligate co-receptor for endogenous FGF23 function. Renal homogenate binding assay, cell-surface binding with forced Klotho expression, in vivo antibody neutralization, reconstitution of FGFR1(IIIc)/Klotho complex Nature High 17086194
2018 Crystal structure of a 1:1:1 ternary complex of shed α-klotho ectodomain, FGFR1c ligand-binding domain, and FGF23 shows that α-klotho simultaneously tethers FGFR1c via its D3 domain and FGF23 via its C-terminal tail, conferring complex stability. Dimerization and receptor activation still require heparan sulfate. The α-klotho structure is incompatible with glycosidase activity, establishing it as a non-enzymatic scaffold protein. X-ray crystallography (atomic structure of ternary complex), structural functional validation Nature High 29342138
2011 FGF23 causes pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway in a klotho-independent manner. Intramyocardial or intravenous FGF23 injection in wild-type mice produced LVH. Treatment with an FGF-receptor blocker attenuated LVH in a CKD model. Isolated rat cardiomyocyte hypertrophy assay, intramyocardial/intravenous FGF23 injection in mice, FGF-receptor blocker treatment in CKD animal model, klotho-deficient mouse model The Journal of clinical investigation High 21985788
2017 FGF23 induces cardiac hypertrophy and LVH specifically via FGFR4 (not other FGFRs); specific pharmacological blockade of FGFR4 attenuated established LVH in the 5/6 nephrectomy CKD rat model and protected aging mice from LVH. FGF23 also increases cardiac contractility via FGFR4. FGFR4-specific pharmacological blockade in CKD rat model (5/6 nephrectomy), FGFR4 knockout aging mice, in vitro cardiomyocyte assays Scientific reports High 28512310
2014 FGF23 directly regulates membrane abundance of the Na+:Cl- cotransporter NCC in distal renal tubules via a signaling cascade involving the FGF receptor/αKlotho complex → ERK1/2 → SGK1 → WNK4. Gain of FGF23 function increased distal tubular Na+ uptake and NCC membrane expression, causing volume expansion, hypertension, and cardiac hypertrophy in an αKlotho- and dietary Na+-dependent fashion. NCC inhibitor chlorothiazide abrogated these effects. Recombinant FGF23 injection in wild-type mice, Fgf23- and αKlotho-deficient mouse models, Hyp mice, pharmacological NCC inhibition, western blot for NCC membrane expression EMBO molecular medicine High 24797667
2016 FGF23 inhibits neutrophil (PMN) recruitment by binding FGFR2 on PMNs, activating protein kinase A (PKA), and thereby inhibiting activation of the small GTPase Rap1, which counteracts selectin- and chemokine-triggered β2 integrin activation. FGF23 neutralization in CKD mice restored leukocyte recruitment; FGFR2 knockdown on PMNs rescued host defense. Intravital microscopy, in vitro PMN adhesion/arrest/migration assays, FGF23 neutralization in CKD mouse models, FGFR2 knockdown, PKA knockdown The Journal of clinical investigation High 26878171
2005 FGF23-induced reductions in renal NaPi2a (sodium-phosphate cotransporter type IIa) expression and 1α-hydroxylase mRNA are independent of the 1,25(OH)2D/VDR signaling system, demonstrated by FGF23 administration to VDR-null mice. FGF23 production is regulated by VDR-independent pathways including calcium, whereas dietary phosphate-stimulated FGF23 production required VDR. Recombinant FGF23 administration to VDR knockout mice, measurement of NaPi2a protein abundance, 1α-hydroxylase and 24-hydroxylase mRNA, dietary manipulation American journal of physiology. Renal physiology High 15998839
2020 Kidney-derived glycerol-3-phosphate (G-3-P) stimulates bone and bone marrow FGF23 production through local GPAT-mediated lysophosphatidic acid (LPA) synthesis, which acts via LPA receptor 1 (LPAR1). Acute kidney injury rapidly increased circulating G-3-P, and the AKI-induced rise in FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Aptamer-based proteomics and LC-MS metabolomics of human renal venous plasma, exogenous G-3-P administration in mice, GPAT inhibition, Lpar1 genetic deletion, AKI mouse models The Journal of clinical investigation High 32065590
2023 C-terminal FGF23 (Cter-FGF23) cleaved peptides, derived mainly from osteocytes via furin-dependent cleavage, bind BMP2 and BMP9 and prevent BMP-induced hepcidin production in the liver, thereby increasing iron availability during acute inflammation. Osteocyte-specific Fgf23 deletion and osteocyte-specific Furin deletion both reduced Cter-FGF23 and worsened iron deficiency during inflammation. Osteocyte-specific Fgf23 and Furin knockout mice, co-administration of Cter-FGF23 with BMP2/BMP9, genetic overexpression of Cter-Fgf23, measurement of hepcidin and serum iron Blood High 37053547
2021 FGF23 undergoes FAM20C-mediated phosphorylation that targets it to proteolysis by the subtilisin-like proprotein convertase FURIN, resulting in secretion of FGF23 fragments. O-glycosylation of FGF23 by GALNT3 prevents this proteolysis, resulting in secretion of biologically active intact FGF23. Review synthesizing genetic/biochemical evidence from prior studies; described as established mechanisms from multiple prior works Journal of molecular endocrinology Medium 33338030
2014 Pro-inflammatory cytokines TNF, IL-1β, TWEAK, and bacterial LPS up-regulate Fgf23 mRNA in osteocyte-like IDG-SW3 cells and human bone via NF-κB-dependent mechanisms. These stimuli also increased GALNT3 expression (which protects FGF23 from cleavage), and intact FGF23 protein increased in the presence of furin inhibitors, indicating that furin-mediated cleavage critically controls active FGF23 secretion. IDG-SW3 osteocyte cell line stimulation, human bone samples, qRT-PCR, ELISA, NF-κB inhibition, furin inhibition assays Molecular and cellular endocrinology Medium 25458698
2014 Osteocyte-specific deletion of FGFR1 (Fgfr1Dmp1-cKO) reduced FGF23 expression in bone by 50% and serum FGF23 by 3-fold. FGF23 promoter activity in osteoblasts was stimulated by FGFR1 activation and inhibited by dominant-negative FGFR1(TK-), PLCγ, and MAPK inhibitors. FGF2 stimulated FGF23 translation via a FGFR1- and PI3K/Akt-dependent mechanism, establishing autocrine/paracrine FGFR1 signaling as a regulator of FGF23 production. Osteocyte-specific conditional Fgfr1 knockout (Dmp1-Cre), TOPflash luciferase reporter, FGF23 promoter-luciferase assay, dominant-negative FGFR1 overexpression, pharmacological pathway inhibitors PloS one High 25089825
2010 FGF23 activates the Raf/MEK/ERK signaling pathway and induces EGR1 expression via FGFR1 in HEK293 cells, and also phosphorylates FRS2α. Extracellular phosphate activates the same cascade via PiT-1 (type III Na+/Pi cotransporter) converging on FGFR1, with FGFR1 knockdown abolishing Pi-induced ERK1/2 and FRS2α phosphorylation. HEK293 cell transfection with recombinant proteolysis-resistant FGF23[R179Q], ERK1/2 phosphorylation assays, FRS2α phosphorylation, FGFR1 knockdown, FGFR1 overexpression, PiT-1 knockdown, MEK inhibitor Journal of cellular biochemistry Medium 20717920
2009 FGF23 acts on the parathyroid gland via the Klotho-FGFR1c receptor complex to decrease PTH mRNA expression and PTH secretion through activation of the MAPK pathway. In CKD, parathyroid resistance to FGF23 is caused by down-regulation of the Klotho-FGFR1 complex in hyperplastic parathyroid glands. Parathyroid cell experiments, MAPK pathway activation assays, Klotho-FGFR1 expression analysis in CKD parathyroid tissue (human and animal) Kidney international Medium 20010546
2012 FGF23 acts directly on the parathyroid gland via the Klotho-FGFR1 complex to decrease PTH synthesis and secretion through activation of the MAPK pathway. In advanced experimental uremia, parathyroids do not respond to administered FGF23 by MAPK activation or PTH inhibition, correlating with down-regulation of parathyroid Klotho-FGFR1. PTH directly increases FGF23 expression by osteoblast-like cells, and parathyroidectomy reduces FGF23 in CKD models. FGF23 administration to uremic rats, MAPK pathway activation assays in parathyroid tissue, parathyroidectomy experiments, osteoblast culture with PTH Advances in experimental medicine and biology Medium 22396164
2015 Phosphate directly enhances Fgf23 transcription in UMR-106 osteoblastic cells by stimulating NADPH oxidase-induced reactive oxygen species (ROS) production, which activates the MEK-ERK signaling pathway. Phosphonoformate (sodium-phosphate cotransporter inhibitor), NADPH oxidase inhibitor apocynin, and MEK inhibitor PD98059 all blocked phosphate-induced Fgf23 expression and promoter activity. Phosphate did not affect Fgf23 mRNA stability. UMR-106 cell culture, Fgf23 promoter-luciferase assay, ROS measurement (fluorescence), pharmacological inhibitors (apocynin, PD98059, phosphonoformate), mRNA stability assay Journal of bone and mineral metabolism Medium 25792238
2016 Aldosterone up-regulates Fgf23 transcription and secretion via mineralocorticoid receptor activation, involving SGK1, NF-κB, and store-operated Ca2+ entry (SOCE). In osteoblastic UMR-106 cells, aldosterone enhanced SOCE and Fgf23 mRNA, effects reversed by mineralocorticoid receptor blockers (spironolactone, eplerenone), SGK1 inhibitor, NF-κB inhibitor, and Ca2+ channel blocker. In vivo, DOCA treatment and salt depletion elevated serum FGF23. UMR-106 cell culture, Fura-2 Ca2+ imaging, SOCE measurement, qRT-PCR, DOCA treatment and salt depletion in mice, serum FGF23 ELISA Biochemical and biophysical research communications Medium 26773502
2019 FGF23 promotes cardiac hypertrophy via FGF receptor 4-dependent activation of phospholipase Cγ/calcineurin/NFAT signaling, independent of klotho. FGF23 expressed in cardiac myocytes also stimulates pro-fibrotic factors in myocytes to induce fibrosis-related pathways in fibroblasts in a paracrine manner. In vitro neonatal rat ventricular myocyte (NRVM) hypertrophy assays, FGFR4 blockade, PLCγ/calcineurin/NFAT pathway analysis, co-culture experiments Frontiers in endocrinology Medium 29892269
2019 FGF23-mediated activation of local renin-angiotensin-aldosterone system (RAAS) in the heart promotes cardiac hypertrophy and fibrosis. In neonatal rat ventricular myocytes and fibroblasts, FGF23 stimulated RAAS gene expression; FGF23-mediated hypertrophy and NFAT target gene induction were attenuated by cyclosporine A, losartan, and spironolactone. FGF23 also induced TGF-β and CTGF in cardiac fibroblasts, suppressed by losartan and spironolactone. 5/6 nephrectomy rat model, neonatal rat ventricular myocytes and cardiac fibroblasts (NRVM, NRCF), qPCR, western blot, pharmacological inhibition (losartan, spironolactone, cyclosporine A) International journal of molecular sciences Medium 31540546
2018 FGF23 activates nuclear Ca2+-regulated CaMKII-HDAC4 pathway and induces IP3-mediated Ca2+ release from nucleoplasmic Ca2+ stores in neonatal rat ventricular myocytes (NRVMs), similar to angiotensin II. FGF23-induced hypertrophy was attenuated by losartan (ATII receptor antagonist), and FGF23 increased intracellular ATII peptide expression and secretion in NRVMs, suggesting FGF23-mediated hypertrophy involves local angiotensin II production. NRVM Ca2+ imaging, cell area measurement, hypertrophic gene expression, losartan treatment, ATII peptide measurement Cellular and molecular life sciences : CMLS Medium 30062428
2021 During acute kidney injury, hepatic FGF23 production is driven by the orphan nuclear receptor ERR-γ, which is induced by circulating IL-6. Ectopic ERR-γ overexpression was sufficient to induce hepatic FGF23. Liver-specific ERRγ knockout or ERRγ inverse agonist treatment decreased hepatic FGF23 mRNA and plasma FGF23 levels in AKI mice. Folic acid-induced AKI mouse model, liver-specific ERRγ knockout, ERRγ overexpression, IL-6 neutralizing antibody and recombinant IL-6 administration, ERRγ inverse agonist Proceedings of the National Academy of Sciences of the United States of America High 33853949
2024 Hepatic FGF23 is transcriptionally regulated by ERR-γ in response to alcohol-mediated activation of cannabinoid receptor type 1 (CB1R). FGF23-LKO mice showed decreased hepatic CYP2E1 expression, reduced oxidative stress, and improved alcoholic liver disease, establishing a CB1R-ERRγ-FGF23-CYP2E1 axis in alcoholic liver injury. Hepatocyte-specific knockouts (CB1R-LKO, ERRγ-LKO, FGF23-LKO), chronic alcohol feeding, ERRγ inverse agonist treatment, CYP2E1 expression analysis, liver injury assessment Redox biology High 38479224
2015 FGF23 signals through a klotho/FGFR complex in multiple myeloma cells (expressing both klotho and FGFR), increasing EGR1 and its target heparanase mRNA. FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23 and suppressed myeloma growth in bone. MM cell line stimulation with FGF23, mRNA expression (EGR1, heparanase), FGFR inhibitor NVP-BGJ398, in vivo bone growth model, klotho/FGFR expression analysis by IHC and western blot Oncotarget Medium 25944690
2020 High extracellular phosphate directly activates FGFR1 in osteocytes/osteoblasts, and downstream intracellular signaling regulates GALNT3 expression, which in turn controls O-glycosylation and the ratio of intact to cleaved FGF23. FGFR1 thus functions as a phosphate-sensing receptor in the regulation of FGF23 production. Cell culture experiments with phosphate stimulation, FGFR1 activation assays, GALNT3 expression analysis, FGF23 protein cleavage measurements Journal of endocrinological investigation Low 32140858
2019 FGF23 deficiency in mice leads to hippocampal-dependent cognitive impairment (dose-dependent, established by behavioral testing) without gross structural or developmental brain defects, without change in hippocampal synaptic plasticity, and with only minor impairment to postnatal hippocampal neurogenesis, indicating a distinct brain phenotype from Klotho-deficient mice. Fgf23-deficient mouse model, hippocampal-dependent behavioral tests (cognitive), hippocampal neurogenesis assay, synaptic plasticity measurements eNeuro Medium 30911673
2021 C-terminal FGF23 (Cter-FGF23) peptide alleviates LPS-induced acute hypoferremia by reducing hepatic and circulating hepcidin. FGF23 is induced as early as pro-inflammatory cytokines by LPS (TLR4 activation), and inhibition of FGF23 signaling with C-terminal FGF23 tail abrogated iron sequestration in liver and spleen. Wild-type mouse LPS model, C-terminal FGF23 peptide administration, hepcidin mRNA and protein measurement, serum iron and transferrin saturation, tissue iron quantification Haematologica Medium 32193252
2015 FGF23 up-regulates AHSG (Fetuin-A) mRNA and protein production in osteocytes via FGF receptor-dependent mechanisms; FGF23 silencing had the opposite effect. FGF23 and AHSG proteins co-localize in both cytoplasm and nucleus of osteocytes, suggesting possible direct interaction. Osteocyte cell culture, FGF23 addition/overexpression/silencing, qRT-PCR, western blot, FGF23 receptor blockade, co-localization by immunofluorescence Bone Low 26476373

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 FGF23 induces left ventricular hypertrophy. The Journal of clinical investigation 1610 21985788
2006 Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 1454 17086194
2010 Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annual review of medicine 504 20059333
2018 α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 390 29342138
2009 The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nature reviews. Endocrinology 341 19844248
2005 Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. American journal of physiology. Renal physiology 279 15998839
2014 FGF23 regulates renal sodium handling and blood pressure. EMBO molecular medicine 256 24797667
2003 FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. American journal of physiology. Endocrinology and metabolism 251 12791601
2016 FGF23 signaling impairs neutrophil recruitment and host defense during CKD. The Journal of clinical investigation 230 26878171
2019 FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet journal of rare diseases 222 30808384
2012 Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Experimental cell research 210 22421513
2013 Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nature reviews. Nephrology 209 23774819
2018 FGF23 Actions on Target Tissues-With and Without Klotho. Frontiers in endocrinology 157 29770125
2016 Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease. Kidney diseases (Basel, Switzerland) 153 28785560
2014 Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Molecular and cellular endocrinology 147 25458698
2021 FGF23 signalling and physiology. Journal of molecular endocrinology 137 33338030
2016 FGF23-Klotho signaling axis in the kidney. Bone 131 27622885
2011 Phosphate and FGF-23. Kidney international. Supplement 124 21346724
2009 Overview of the FGF23-Klotho axis. Pediatric nephrology (Berlin, Germany) 124 19626341
2009 FGF23-parathyroid interaction: implications in chronic kidney disease. Kidney international 123 20010546
2013 Arterial klotho expression and FGF23 effects on vascular calcification and function. PloS one 114 23577141
2012 Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Critical reviews in eukaryotic gene expression 114 22339660
2020 Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney. The Journal of clinical investigation 112 32065590
2017 FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Scientific reports 103 28512310
2004 The wrickkened pathways of FGF23, MEPE and PHEX. Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists 102 15470265
2018 X-Linked Hypophosphatemia and FGF23-Related Hypophosphatemic Diseases: Prospect for New Treatment. Endocrine reviews 99 29381780
2023 FGF23 and klotho at the intersection of kidney and cardiovascular disease. Nature reviews. Cardiology 98 37443358
2010 Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. Clinical journal of the American Society of Nephrology : CJASN 98 20798257
2009 Novel regulators of Fgf23 expression and mineralization in Hyp bone. Molecular endocrinology (Baltimore, Md.) 98 19556340
2014 Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PloS one 95 25089825
2012 FGF23 production by osteocytes. Pediatric nephrology (Berlin, Germany) 92 22983423
2005 FGF23 and disorders of phosphate homeostasis. Cytokine & growth factor reviews 92 15863037
2018 Paracrine Effects of FGF23 on the Heart. Frontiers in endocrinology 87 29892269
2015 FGF23 promotes prostate cancer progression. Oncotarget 83 26019137
2016 Ironing out the cross talk between FGF23 and inflammation. American journal of physiology. Renal physiology 82 27582104
2019 FGF23-Mediated Activation of Local RAAS Promotes Cardiac Hypertrophy and Fibrosis. International journal of molecular sciences 81 31540546
2016 Update on FGF23 and Klotho signaling. Molecular and cellular endocrinology 81 27178987
2023 Regulation of FGF23 production and phosphate metabolism by bone-kidney interactions. Nature reviews. Nephrology 80 36624273
2017 FGF23 and Left Ventricular Hypertrophy in Children with CKD. Clinical journal of the American Society of Nephrology : CJASN 78 29025789
2020 Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease. Toxins 76 32188018
2012 The role of FGF23 in CKD--with or without Klotho. Nature reviews. Nephrology 75 22714041
2016 Up-regulation of FGF23 release by aldosterone. Biochemical and biophysical research communications 74 26773502
2016 FGF23-αKlotho as a paradigm for a kidney-bone network. Bone 72 27847255
2010 Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. Journal of cellular biochemistry 72 20717920
2014 New insights into the FGF23-Klotho axis. Seminars in nephrology 68 25498378
2021 FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment. Journal of molecular endocrinology 64 33295878
2016 The FGF23 and Klotho system beyond mineral metabolism. Clinical and experimental nephrology 64 27838783
2008 PHEX, FGF23, DMP1 and beyond. Current opinion in nephrology and hypertension 64 18660670
2019 Physiology of FGF23 and overview of genetic diseases associated with renal phosphate wasting. Metabolism: clinical and experimental 61 30664852
2018 FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator? Frontiers in endocrinology 60 30013515
2019 Regulation of fibroblast growth factor 23 (FGF23) in health and disease. FEBS letters 59 31199502
2010 FGF23 and the parathyroid glands. Pediatric nephrology (Berlin, Germany) 58 20526631
2012 FGF23 and syndromes of abnormal renal phosphate handling. Advances in experimental medicine and biology 53 22396161
2022 PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond. Frontiers in endocrinology 52 36246903
2012 The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled. Cell biochemistry and function 52 22573484
2018 Klotho-FGF23, Cardiovascular Disease, and Vascular Calcification: Black or White? Current vascular pharmacology 51 28294047
2016 FGF23 from bench to bedside. American journal of physiology. Renal physiology 51 26864938
2018 Phosphate Homeostasis, Inflammation and the Regulation of FGF-23. Kidney & blood pressure research 50 30504710
2019 FGF23, Biomarker or Target? Toxins 48 30909513
2015 Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells. Journal of bone and mineral metabolism 48 25792238
2021 FGF23 and Vitamin D Metabolism. JBMR plus 47 34950827
2019 FGF23 and Associated Disorders of Phosphate Wasting. Pediatric endocrinology reviews : PER 47 31599133
2020 Osteocytic FGF23 and Its Kidney Function. Frontiers in endocrinology 45 32982979
2022 The regulation of FGF23 under physiological and pathophysiological conditions. Pflugers Archiv : European journal of physiology 44 35084563
2019 FGF23, Hypophosphatemia, and Emerging Treatments. JBMR plus 44 31485552
2011 Phosphate and FGF-23. Kidney international 42 26746858
2019 FGF-23 Deficiency Impairs Hippocampal-Dependent Cognitive Function. eNeuro 40 30911673
2018 FGF23 beyond Phosphotropic Hormone. Trends in endocrinology and metabolism: TEM 40 30217676
2015 FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells. Oncotarget 40 25944690
2015 FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes. The Journal of endocrinology 40 26148725
2023 Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation. Blood 38 37053547
2020 Phosphate-sensing and regulatory mechanism of FGF23 production. Journal of endocrinological investigation 38 32140858
2018 Crosstalk between FGF23- and angiotensin II-mediated Ca2+ signaling in pathological cardiac hypertrophy. Cellular and molecular life sciences : CMLS 38 30062428
2021 Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer. Frontiers in cell and developmental biology 37 33520985
2019 FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model. JCI insight 37 31801907
2018 FGF23C-tail improves diabetic nephropathy by attenuating renal fibrosis and inflammation. BMC biotechnology 37 29843712
2016 Extrarenal effects of FGF23. Pediatric nephrology (Berlin, Germany) 37 27704252
2012 FGF23, klotho and vitamin D interactions: What have we learned from in vivo mouse genetics studies? Advances in experimental medicine and biology 36 22396163
2024 ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress. Redox biology 35 38479224
2021 Regulation of FGF23: Beyond Bone. Current osteoporosis reports 35 34757587
2009 FGF-23 in bone biology. Pediatric nephrology (Berlin, Germany) 35 20012997
2012 Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant SPAK. Kidney & blood pressure research 34 23235437
2019 The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research. Frontiers in physiology 33 30971944
2017 Pleiotropic Actions of FGF23. Toxicologic pathology 33 29096595
2016 Fgf23 and parathyroid hormone signaling interact in kidney and bone. Molecular and cellular endocrinology 33 27498418
2016 The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis. Hormone molecular biology and clinical investigation 32 26943611
2015 FGF23-regulated production of Fetuin-A (AHSG) in osteocytes. Bone 32 26476373
2013 Parathyroid function in chronic kidney disease: role of FGF23-Klotho axis. Contributions to nephrology 31 23652554
2021 C-FGF23 peptide alleviates hypoferremia during acute inflammation. Haematologica 30 32193252
2019 Cardiac FGF23: new insights into the role and function of FGF23 after acute myocardial infarction. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 29 30852297
2021 Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury. Proceedings of the National Academy of Sciences of the United States of America 28 33853949
2019 Vitamin D sterols increase FGF23 expression by stimulating osteoblast and osteocyte maturation in CKD bone. Bone 27 31377240
2020 Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 26 31968132
2019 αKlotho-FGF23 interactions and their role in kidney disease: a molecular insight. Cellular and molecular life sciences : CMLS 25 31350618
2012 FGF23 and the parathyroid. Advances in experimental medicine and biology 25 22396164
2020 Influence of FGF23 and Klotho on male reproduction: Systemic vs direct effects. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 32729975
2018 FGF23 and Fetuin-A Interaction in the Liver and in the Circulation. International journal of biological sciences 23 29904273
2018 Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC). Scientific reports 22 29483574
2016 The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders. Vitamins and hormones 22 27125741
2015 FGF23 regulation of renal tubular solute transport. Current opinion in nephrology and hypertension 22 26125643

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