How Fibroblast Growth Factor 23 Works

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 Fibroblast Growth Factor 23 Gene and Protein StructureThe fibroblast growth factor (FGF) family consists of 22 members with varied functions (2). FGF23 is an approximately 32-kD (251 amino acids) protein with an N-terminal region that contains the FGF homology domain and a novel 71-amino acid C-terminus that was originally discovered by homology-based PCR screening of a mouse embryonic cDNA library (3). The FGF23 gene is located on Chr 12p13 and is phylogenetically grouped with FGF19 and 21 gene products (2,3), with which it has approximately 24% and approximately 22% amino acid identities, respectively. FGF23 principally acts as a phosphaturic factor and suppressor of 1␣-hydroxylase activity in the kidney (4,5), making it functionally distinct from other members of this family. Tissue Expression and Function: Evidence for a Bone-Kidney AxisFGF23 is predominately expressed in osteocytes in bone (6,7), but it is also expressed in pericyte-like cells that surround the venous sinuses in the bone marrow, in the ventrolateral thalamic nucleus, and in thymus and lymph nodes (Figure 1). The relative contribution of these sites to circulating FGF23 levels is not known, but the high levels of expression in the osteocyte and that osteocytes are the most abundant cell in bone suggest that the serum levels of FGF23 are derived mainly from bone. In addition, the production of FGF23 by osteocytes, cells that are central to the regulation of osteoblast function and mineralization, likely has functional significance (8). In this regard, osteocytes secrete sclerostin, an inhibitor of bone formation and the phosphaturic factor FGF23, as well as other gene products, such as phosphate-regulating endopeptidase homolog, X-linked (Phex), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE), that regulate bone mineralization and FGF23 expression. Phex is a type I cell surface zinc metalloprotease that is involved in the regulation of FGF23 levels and is mutated in X-linked hypophosphatemic rickets (9). Both DMP1 and MEPE are glycophosphoproteins that belong to the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins. MEPE and DMP1 are predominately expressed in bones and/or teeth, where they respectively inhibit and induce mineralization of extracellular matrix (10). These associations suggest that osteocytes coordinate osteoblast-mediated bone formation with renal regulation of systemic phosphate homeostasis through the regu...

Functional evolutionary history of the mouse Fgf gene family

“…In addition, acidic glycosaminoglycans in the form of heparan sulfate proteoglycans function to retain these FGFs in the vicinity of FGF-producing sites, such that they primarily act in a paracrine manner. By contrast, the hFGFs have low-affinity heparin-binding sites and have been found to act in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto and Yamashita, 2007;Liu and Quarles, 2007).…”

“…In addition, acidic glycosaminoglycans limit the diffusion of FGFs, localizing their activity to the vicinity of FGF-producing cells (Flaumenhaft et al, 1990). In contrast, hFGFs have poor heparin-binding affinity and act on target cells far from their site of production in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto et al, 2007;Liu et al, 2007). In addition, FGF15, FGF21, and FGF23 require co-receptors, Klotho or ␤Klotho, to activate FGFRs (Ogawa et al, 2007;Urakawa et al, 2006).…”

FGF-23: estado da arte

“…30 The relative contribution of those tissues to FGF-23 expression is unknown, but the high levels of expression by osteocytes suggest that the bone tissue is the major source of FGF-23. 2 For FGF-23 to exert its phosphaturic effect and reduce 1α,25(OH) 2 D 3 levels, it has to bind to one of the four receptors of the FGF receptor (FGFR) family. 2 Heparin sulfate proteoglycans and Klotho protein act on that binding as cofactors.…”

“…2 For FGF-23 to exert its phosphaturic effect and reduce 1α,25(OH) 2 D 3 levels, it has to bind to one of the four receptors of the FGF receptor (FGFR) family. 2 Heparin sulfate proteoglycans and Klotho protein act on that binding as cofactors. Klotho protein is a type I membrane protein containing 1014 amino acids and is mainly expressed in the renal proximal tubules, parathyroid gland, and choroid plexus of the brain.…”

“…Its currently known functions involve the phosphorus (P) metabolism and inhibition of 1α hydroxylase, the enzyme responsible for the synthesis of calcitriol. 2 That discovery led to a better understanding of the mechanisms of P control, an ion associated with mortality, especially in chronic kidney disease (CKD).…”