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Emerging concepts on the FGF23 regulation and activity

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Abstract

Fibroblast growth factor 23 (FGF23) discovery has provided new insights into the regulation of Pi and Ca homeostasis. It is secreted by osteoblasts and osteocytes, and acts mainly in the kidney, parathyroid, heart, and bone. The aim of this review is to highlight the current knowledge on the factors modulating the synthesis of FGF23, the canonical and non-canonical signaling pathways of the hormone, the role of FGF23 in different pathophysiological conditions, and the anti-FGF23 therapy. This is a narrative review based on the search of PubMed database in the range of years 2000–2023 using the keywords local and systemic regulators of FGF23 synthesis, FGF23 receptors, canonical and non-canonical pathways, pathophysiological conditions and FGF23, and anti-FGF23 therapy, focusing the data on the molecular mechanisms. The regulation of FGF23 synthesis is complex and multifactorial. It is regulated by local factors and systemic regulators mainly involved in bone mineralization. The excessive FGF23 production is associated with different congenital diseases and with diseases occurring with a secondary high FGF23 production such as in chronic disease kidney and tumor-induced osteomalacia (TIO). The anti-FGF23 therapy appears to be useful to treat chromosome X-linked hypophosphatemia and TIO, but there are doubts about the handle of excessive FGF23 production in CKD. FGF23 biochemistry and pathophysiology are generating a plethora of knowledge to reduce FGF23 bioactivity at many levels that might be useful for future therapeutics of diseases associated with high-serum FGF23 levels.

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Data Availability

No datasets were generated or analysed during the current study.

Abbreviations

1,25(OH)2D3:

1,25-Dihydroxyvitamin D

ADHR:

Autosomal-dominant hereditary rickets

BMD:

Bone mineral density

Ca:

Calcium

cFGF23:

C-terminal FGF23

CKD:

Chronic kidney disease

DMP1:

Dentin matrix protein 1

EPO:

Erythropoietin

ERK1/2:

Extracellular signal-regulated kinases 1/2

ESRD:

End-stage renal disease

FGFR:

FGF receptor

FGFR1:

FGF receptor 1

GalNT3:

N-acetylgalactosaminyltransferase 3

HIF:

Hypoxia-inducible factor

iFGF23:

Intact FGF23

LVH:

Left ventricular hypertrophy

NFAT:

Nuclear factor of activated T-cells

OB:

Osteoblasts

oc:

Osteocytes

PHEX:

Pi-regulating gene homologous to endopeptidase on X chromosome

Pi:

Phosphate

SGK1:

Serum/glucocorticoid-regulated kinase-1

TIO:

Tumor-induced osteomalacia

TNAP:

Non-tissue-specific alkaline phosphatase

TRPV5:

Transient receptor potential vanilloid 5

VC:

Vascular calcifications

VDR:

Vitamin D receptor

XLH:

Chromosome X-linked hypophosphatemia

Αkl:

αKlotho

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Acknowledgements

This work was supported by grants from FONCYT (PICT-2018-1809), SECYT (UNC), Argentina. Prof. Dr. Nori Tolosa de Talamoni and Dr. Vanessa Areco are Members of Investigator Career from the Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Argentina. The authors thank Darío Talamoni for his corrections in the English language.

Funding

This study was funded by Fondo para la Investigación Científica y Tecnológica (FONCYT), PICT 2018-1809, PICT 2018-1809, PICT 2018-1809, Secretaría de Ciencia y Tecnología (SECYT).

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  1. Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do, Piso, Ciudad Universitaria, 5000, Córdoba, Argentina

    María Angélica Rivoira, María Elena Peralta López, Vanessa Areco, Gabriela Díaz de Barboza & Nori Tolosa de Talamoni

  2. Instituto Multidisciplinario de Investigación y Transferencia Agroalimentaria y Biotecnológica (IMITAB, CONICET-UNVM), Córdoba, Argentina

    Vanessa Areco

  3. Cátedra de Clínica Médica II – UHMI Nº 2, Hospital San Roque, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    María Paula Dionisi

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MAR: Searched literature, Discussed topics, Checked the references, Prepared Figs 1 and 2, and Graphical Abstract MEPL: Searched literature, Discussed topics, VA: Searched literature, Discussed topics, Checked the references GDdeB: Searched literature, Discussed topics, Checked the references MPD: Searched literature, Discussed topics NTdeT: Had the original idea, Searched literature, Discussed topics, Wrote the main manuscript text All authors reviewed the manuscript.

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Rivoira, M.A., Peralta López, M.E., Areco, V. et al. Emerging concepts on the FGF23 regulation and activity. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04982-6

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