Upstream Regulators of Fibroblast Growth Factor 23.

Danielle M A Ratsma,Bram C J Van Der Eerden,M Carola Zillikens

doi:10.3389/fendo.2021.588096

Danielle M A Ratsma, Bram C J Van Der Eerden + Show 1 more

Open Access

https://doi.org/10.3389/fendo.2021.588096

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Abstract

Fibroblast growth factor 23 (FGF23) has been described as an important regulator of mineral homeostasis, but has lately also been linked to iron deficiency, inflammation, and erythropoiesis. FGF23 is essential for the maintenance of phosphate homeostasis in the body and activating mutations in the gene itself or inactivating mutations in its upstream regulators can result in severe chronic hypophosphatemia, where an unbalanced mineral homeostasis often leads to rickets in children and osteomalacia in adults. FGF23 can be regulated by changes in transcriptional activity or by changes at the post-translational level. The balance between O-glycosylation and phosphorylation is an important determinant of how much active intact or inactive cleaved FGF23 will be released in the circulation. In the past years, it has become evident that iron deficiency and inflammation regulate FGF23 in a way that is not associated with its classical role in mineral metabolism. These conditions will not only result in an upregulation of FGF23 transcription, but also in increased cleavage, leaving the levels of active intact FGF23 unchanged. The exact mechanisms behind and function of this process are still unclear. However, a deeper understanding of FGF23 regulation in both the classical and non-classical way is important to develop better treatment options for diseases associated with disturbed FGF23 biology. In this review, we describe how the currently known upstream regulators of FGF23 change FGF23 transcription and affect its post-translational modifications at the molecular level.

Highlights

In 1959 a first mention was made by Andrea Prader of a circulating “rachitonic” substance that was the cause of tumor-induced osteomalacia (TIO)
When the volunteers were subjected to a glucose challenge, the increase in insulin was inversely correlated with fibroblast growth factor 23 (FGF23) levels [114]. Together these results indicate that insulin is an inhibitor of FGF23, at least partially independent of the inflammation associated with diabetes
We distinguish the classical regulation of FGF23 involved in phosphate metabolism and the nonclassical regulation affected by inflammation and iron or insulin levels

Summary

INTRODUCTION

In 1959 a first mention was made by Andrea Prader of a circulating “rachitonic” substance that was the cause of tumor-induced osteomalacia (TIO). In adult Sabra rats, administration of Forskolin, a PKA inhibitor, resulted in decreased levels of SOST mRNA [62] Together, this indicates that activation of the PKA pathway by PTH both directly stimulates FGF23 transcription by increasing NURR1 expression, as well as indirectly by inhibition of SOST (Figure 2). A study by Takashi et al showed that mice fed a high phosphate diet have increased levels of serum Fgf compared to mice on a low phosphate diet [71] They found in UMR106 cells that this was not caused by the upregulation of Fgf transcription, but rather by increased expression of GalNt3, which results in a higher level of active iFGF23 in the circulation [71]. Additional work should reveal the interaction between these hormones in order to add leptin to the definitive list of FGF23 regulators

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CONCLUSION