Article

How Fibroblast Growth Factor 23 Works

University of Kansas, Lawrence, Kansas, United States
Journal of the American Society of Nephrology (Impact Factor: 9.34). 07/2007; 18(6):1637-47. DOI: 10.1681/ASN.2007010068
Source: PubMed

ABSTRACT

There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1,25-dihydroxyvitamin D, soft tissue calcifications, and hyperostosis. Knowledge of the genetic basis of these hereditary disorders of phosphate homeostasis and studies of their mouse homologues have uncovered a bone-kidney axis and new systems biology that govern bone mineralization, vitamin D metabolism, parathyroid gland function, and renal phosphate handling. Further understanding of this primary phosphate homeostatic pathway has the potential to have a significant impact on the diagnosis and treatment of disorders of bone and mineral metabolism.

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    • "The degradative cleavage of FGF23 is thought to be accomplished by a member of the proprotein convertase family, since it is blocked by general convertase inhibitors such as decanoyl RVKRchloromethyl ketone [12] [13], and known human mutations within the convertase cleavage site which remove the convertase consensus site decrease cellular degradative cleavage and enhance release of intact FGF23, resulting in severe bone disease [8] [14]; reviewed in [4]. The mammalian eukaryotic proprotein convertases (reviewed in [15] [16]) constitute a family of serine proteases usually associated with the biosynthesis of secreted proteins; the degradative cleavage of FGF23 is unusual in this regard. "
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    ABSTRACT: FGF23 is an O-glycosylated circulating peptide hormone with a critical role in phosphate homeostasis; it is inactivated by cellular proprotein convertases in a pre-release degradative pathway. We have here examined the metabolism of FGF23 in a model bone cell line, IDG-SW3, prior to and following differentiation, as well as in regulated secretory cells. Labeling experiments showed that the majority of (35)S-labeled FGF23 was cleaved to smaller fragments which were constitutively secreted by all cell types. Intact FGF23 was much more efficiently stored in differentiated than in undifferentiated IDG-SW3 cells. The prohormone convertase PC2 has recently been implicated in FGF23 degradation; however, FGF23 was not targeted to forskolin-stimulatable secretory vesicles in a regulated cell line, suggesting that it lacks a targeting signal to PC2-containing compartments. In vitro, PC1/3 and PC2, but not furin, efficiently cleaved glycosylated FGF23; surprisingly, PC5/6 accomplished a small amount of conversion. FGF23 has recently been shown to be phosphorylated by the kinase FAM20C, a process which was shown to reduce FGF23 glycosylation and promote its cleavage; our in vitro data, however, show that phosphorylation does not directly impact cleavage, as both PC5/6 and furin were able to efficiently cleave unglycosylated, phosphorylated FGF23. Using qPCR, we found that the expression of FGF23 and PC5/6, but not PC2 or furin, increased substantially following osteoblast to osteocyte differentiation. Western blotting confirmed the large increase in PC5/6 expression upon differentiation. FGF23 has been linked to a variety of bone disorders ranging from autosomal dominant hypophosphatemic rickets to chronic kidney disease. A better understanding of the biosynthetic pathway of this hormone may lead to new treatments for these diseases.
    Full-text · Article · Dec 2015 · Bone
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    • "FGF23 and the cognate FGF co-receptor Klotho represent the most fundamental mechanism in the regulation of phosphate balance [1] [2]. Besides phosphate balance regulation , this mechanism is intimately involved in the control of nitric oxide (NO) bio-availability [3] [4] and in the regulation of vascular function in healthy elderly people [5] and in patients with Chronic Kidney Disease (CKD) [6]. "

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    • "It is established, for example, that both DMP1 and PHEX induce a reduction in FGF23 levels by inhibiting the promoter sequences of the FGF23 gene [4] [31]. DMP1 was proposed to act as a transcription factor [61] and MEPE is probably involved in regulating FGF23 indirectly, by inhibiting PHEX [62]. In addition to DMP1 function as a negative regulator of FGF23 production in osteocytes, it is suggested to have a direct role in initiating nucleation associated with mineralized tissue morphology and formation [63] [64]. "
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    ABSTRACT: Body phosphate homeostasis is regulated by a hormonal counter-balanced intestine-bone-kidney axis. The major systemic hormones involved in this axis are parathyroid hormone (PTH), 1,25-dihydroxyvitamin-D, and fibroblast growth factor-23 (FGF23). FGF23, produced almost exclusively by the osteocytes, is a phosphaturic hormone that plays a major role in regulation of the bone remodeling process. Remodeling composite components, bone mineralization and resorption cycles create a continuous influx-efflux loop of the inorganic phosphate (Pi) through the skeleton. This “bone Pi loop,” which is formed, is controlled by local and systemic factors according to phosphate homeostasis demands. Although FGF23 systemic actions in the kidney, and for the production of PTH and 1,25-dihydroxyvitamin-D are well established, its direct involvement in bone metabolism is currently poorly understood. This review presents the latest available evidence suggesting two aspects of FGF23 bone local activity: (a) Regulation of FGF23 production by both local and systemic factors. The suggested local factors include extracellular levels of Pi and pyrophosphate (PPi), (the Pi/PPi ratio), and another osteocyte-derived protein, sclerostin. In addition, 1,25-dihydroxyvitamin-D, synthesized locally by bone cells, may contribute to regulation of FGF23 production. The systemic control is achieved via PTH and 1,25-dihydroxyvitamin-D endocrine functions. (b) FGF23 acts as a local agent, directly affecting bone mineralization. We support the assumption that under balanced physiological conditions, sclerostin, by para- autocrine signaling, upregulates FGF23 production by the osteocyte. FGF23, in turn, acts as a mineralization inhibitor, by stimulating the generation of the major mineralization antagonist—PPi. © 2014 BioFactors, 2014
    Full-text · Article · Nov 2014 · BioFactors
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