A G protein-coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23



He, Qing, Shumate, Lauren T, Matthias, Julia, Aydin, Cumhur, Wein, Marc N, Spatz, Jordan M, Goetz, Regina, Mohammadi, Moosa, Plagge, Antonius ORCID: 0000-0001-6592-1343, Pajevic, Paola Divieti
et al (show 1 more authors) (2019) A G protein-coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23. JCI INSIGHT, 4 (17). 125007-.

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Abstract

Dysregulated actions of bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) result in several inherited diseases, such as X-linked hypophosphatemia (XLH), and contribute substantially to the mortality in kidney failure. Mechanisms governing FGF23 production are poorly defined. We herein found that ablation of the Gq/11α–like, extralarge Gα subunit (XLαs), a product of GNAS, exhibits FGF23 deficiency and hyperphosphatemia in early postnatal mice (XLKO). FGF23 elevation in response to parathyroid hormone, a stimulator of FGF23 production via cAMP, was intact in XLKO mice, while skeletal levels of protein kinase C isoforms α and δ (PKCα and PKCδ) were diminished. XLαs ablation in osteocyte-like Ocy454 cells suppressed the levels of FGF23 mRNA, inositol 1,4,5-trisphosphate (IP3), and PKCα/PKCδ proteins. PKC activation in vivo via injecting phorbol myristate acetate (PMA) or by constitutively active Gqα-Q209L in osteocytes and osteoblasts promoted FGF23 production. Molecular studies showed that the PKC activation–induced FGF23 elevation was dependent on MAPK signaling. The baseline PKC activity was elevated in bones of Hyp mice, a model of XLH. XLαs ablation significantly, but modestly, reduced serum FGF23 and elevated serum phosphate in Hyp mice. These findings reveal a potentially hitherto-unknown mechanism of FGF23 synthesis involving a G protein–coupled IP3/PKC pathway, which may be targeted to fine-tune FGF23 levels.

Item Type: Article
Uncontrolled Keywords: Bone and Bones, Kidney, Osteoblasts, Osteocytes, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Disease Models, Animal, Genetic Predisposition to Disease, Parathyroid Hormone, GTP-Binding Proteins, Protein Kinases, Protein Kinase C, Fibroblast Growth Factors, Recombinant Proteins, RNA, Messenger, Female, Male, Familial Hypophosphatemic Rickets, Fibroblast Growth Factor-23
Depositing User: Symplectic Admin
Date Deposited: 12 Sep 2019 15:37
Last Modified: 19 Jan 2023 00:26
DOI: 10.1172/jci.insight.125007
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3054390