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Daryadel, A.* ; Ruiz, P.A.* ; Gehring, N.* ; Stojanovic, D.* ; Ugrica, M.* ; Bettoni, C.* ; Sabrautzki, S. ; Pastor-Arroyo, E.M.* ; Frey-Wagner, I.* ; Lorenz-Depiereux, B. ; Strom, T.M.* ; Hrabě de Angelis, M. ; Rogler, G.* ; Wagner, C.A.* ; Rubio-Aliaga, I.*

Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage.

FASEB J. 35:e21302 (2021)
Postprint DOI PMC
Open Access Green
Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C-terminal FGF23 circulating levels, the inactive C-terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin-NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C-terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Fgf23 ; Jak/stat Signaling ; Pth ; Calcitriol ; Inflammation; Growth-factor 23; Elevated Fgf23; Expression; Phosphate; Kidney; Transport; Hypophosphatemia; Mechanisms; Resistance; Mutations
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Journal FASEB Journal
Quellenangaben Volume: 35, Issue: 2, Pages: , Article Number: e21302 Supplement: ,
Publisher Wiley
Publishing Place Bethesda, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CF Comparative Medicine (CF-Comparative Medicine)
Institute of Epidemiology II (EPI2)
Institute of Experimental Genetics (IEG)
Institute of Human Genetics (IHG)
Grants University of Zurich
Core