Fibroblast Growth Factor 23

Abstract

A lthough phosphate is important in skeletal mineralization, energy metabolism, and multiple enzymatic processes, little has been understood about the regulation of phosphate in health and disease until recently. Genetic and acquired disorders of phosphate homeostasis have begun to reveal important mechanisms for the regulation of phosphate metabolism. Candidate phosphate-regulating hormones ("phosphatonins") have been discovered, and their actions and interactions continue to be elucidated in an exciting area of ongoing clinical and basic research. Autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), and fibrous dysplasia (FD) have similar phenotypes of hypophosphatemia, urinary phosphate wasting as measured by a low tubular maximum reabsorption of phosphate per deciliter of glomerular filtrate (TmP/GFR), osteomalacia, and rickets. The phenotypic similarities suggest a common metabolic pathophysiology. In addition, recent evidence concerning tumoral calcinosis, which results in hyperphosphatemia, inappropriately elevated calcitriol concentrations, and soft tissue calcifications and can be considered the phenotypic "converse" of the phosphate wasting disorders, indicates that this disorder may result from perturbations of some of the same metabolic pathways. Fibroblast growth factor 23 (FGF23) is a recently discovered, novel, secreted protein hormone involved in the pathogenesis of these disorders. This review focuses on the relationship of FGF23 to various disorders of phosphate homeostasis and its potential regulation and function in normal physiology. Hypophosphatemic DisordersADHR ADHR, initially described by Bianchine et al. (1), is characterized by renal phosphate wasting, hypophosphatemia, low or inappropriately normal calcitriol concentrations, and osteomalacia. Econs and McEnery (2) described a large ADHR kindred. Affected patients presented either in childhood with hypophosphatemia and rickets, which resulted in lower extremity deformities, or after puberty with hypophosphatemic osteomalacia, manifesting in weakness, fatigue, bone pain, and fractures. Patients with adult onset of symptoms clinically resemble TIO, but the disease is not a paraneoplastic process. To date, delayed onset of clinically evident disease has been observed only in female individuals. ADHR also exhibits incomplete penetrance, and, in some cases, the clinical and biochemical phenotype spontaneously resolved in patients who were previously documented to have hypophosphatemic rickets (2).The ADHR consortium used the positional cloning approach to identify the gene responsible for ADHR, FGF23 (3). ADHR results from mutations in either arginine 176 or arginine 179 in FGF23. These arginines make up an RXXR cleavage site, and mutations in either of these arginines protect the protein from degradation, potentially increasing the circulating concentration of FGF23 and, thereby, leading to the disease phenotype (4 -6). FGF23 is a 251-amino acid protein in the FGF fa...

Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin

“…Also, the levels of 1,25 vitamin D3 remained inappropriately normal in all hyp mice groups (treated and untreated), and the levels of FGF23 also remained high. It is likely that the persistent hypophosphatemia in treated mice was due to the interplay of additional phosphaturic factors (FGF23, sFRP4 or FGF7; [6,9,38,88]) unaffected by CA074 or pepstatin. Thus, although the ASARM peptide is phosphaturic when administered to normal animals, it may well play a peripheral or component role in the hypophosphatemia in hyp mice.…”

“…This and other data implicate these molecules as potential downstream factors for the pathogenesis of the renal and skeletal abnormalities. Although the physiological or pathophysiological pathway(s) that link PHEX, FGF23 and MEPE still remain to be determined, evidence overwhelmingly suggests that excess full-length FGF23 is responsible for directly or indirectly mediating the hypophosphatemia and reduced serum 1,25 vitamin D3 in HYP [38,78,83,88]. Also, MEPE inhibits phosphate uptake and mineralization in vivo and in vitro [17,69,71] and is involved in extracellular matrix mineralization.…”

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

“…Clinical manifestations of hypophosphatemia include respiratory failure, cardiac arrhythmia, hemolysis, rhabdomyolysis, seizures, and coma acutely and myalgia and osteomalacia chronically (3). Hypophosphatemia originates from diverse pathophysiologic mechanisms, most importantly from renal phosphate wasting, an inherited or acquired condition in which renal tubular reabsorption of phosphate is impaired (5,6).…”

FGF23 and Phosphate Wasting Disorders

“…The mutations, which involve the proprotein convertase (furin) cleavage site, prevent the proteolytic processing of FGF23 to its inactive N-and C-terminal peptides. Mutant FGF23 proteins exhibit increased stability, are more active than wild-type FGF23, in vivo (70)(71), and are likely present at elevated concentrations in ADHR patients (72). Thus, in ADHR patients, high circulating levels of FGF23 are due to decreased FGF23 degradation.…”