fibroblast growth factor 23 usmle
Alterations in local phosphate concentrations in bone can also regulate FGF-23. FGF23 also inhibits PTH, while 1,25(OH)D and PTH stimulate FGF23, completing a feedback loop (Fig. Phex, which colocalizes with FGF-23 in osteocytes, is positioned to coordinate both FGF-23 production and mineralization of extracellular matrix in bone. [7] Thus, FGF23 decreases the reabsorption of calcium and increases excretion of phosphate. Answering these questions may lead to better treatment for diseases with deranged mineral and bone metabolism. pmid:15613425 . FGF23 requires a transmembrane protein cofactor, Klotho, which enables the activation of FGF receptors (FGFR).70 Ectopic calcification, high levels of 1,25(OH)2D3, and hyperphosphatemia were discovered in the phenotypes of Klotho and FGF23 null mice.71–76 Upon activation, FGF23 lowers serum phosphate levels and increases phosphate excretion in the urine by suppressing reabsorption through the action of sodium-phosphate cotransporters, mostly in the renal proximal (Fig. In turn, FGF23 acts through FGF receptors, with Klotho as coreceptor, to inhibit renal P reabsorption, 1,25(OH)2D synthesis, and parathyroid PTH secretion.43,47 FGF23 synergizes with PTH to increase renal P excretion by reducing expression of renal NaPi-IIa and NaPi-IIc in the proximal tubules. Both low bone turnover and impaired mineralization would impair bone buffering capacity, whereas increased calcium and phosphate efflux from increased bone resorption would potentially lead to adaptive renal responses to excrete greater amounts of phosphate. High serum phosphate (phosphorus) concentrations stimulate FGF23 expression and secretion through a yet poorly understood mechanism. Other investigators report direct signaling in the PCT. The iFGF23/cFGF23 ratio was very low due to the fragmentation of FGF23 during the early postpartum period, possibly indicating a considerable contribution to the P homeostasis in the healthy term infants.48. Autosomal dominant hypophosphatemic rickets is caused by mutations in the RXXR domain of FGF-23 that prevents its cleavage and inactivation by subtilisin-like proprotein convertases [53], whereas autosomal recessive hypophosphatemic rickets (ARHR) and XLH [54] are caused by inactivating mutations of DMP1 and PHEX, two genes that regulate the mineralization process. Bouma-de Krijger A(1), Vervloet MG(2). Within the renal proximal tubular epithelium, recent findings imply that FGF23 activates FGFR1 as well as FGFR4, which mediates signaling involving JAK3.49 In the distal tubular epithelium, FGF23 targets with-no-lysine kinase-4 (WNK4) which regulates solute transport.15,49 FGF23 also downregulates synthesis of 1α-hydroxylase in the renal proximal tubules, thus suppressing 1,25(OH)2D3 production. FGF-23 and PTH also interact. 20 Klotho expression is decreased in CKD patients and results in an early decrease in serum klotho concentration. The authors also described narrowed growth plates with decreased numbers of hypertrophic chondrocytes. Using multiple methodologies, FGF-23 has been demonstrated to trigger intracellular signaling via MAPK and extracellular signal-regulated kinase (ERK) phosphorylation. FGF23 is made by osteocytes, a subgroup of osteoblasts that are interconnected through a series of cannuliculi within cancellous (trabecular) bone. High serum FGF 23 levels stimulate FGF 23 expression. [5][6], The main function of FGF23 seems to be regulation of phosphate concentration in plasma. Fibroblast growth factor-23 (FGF23) is a bone-derived hormone suppressing phosphate reabsorption and vitamin D hormone synthesis in the kidney. FGF23 is secreted by osteocytes in response to increased calcitriol. [4] FGF23 is a member of the fibroblast growth factor (FGF) family which participates in phosphate and vitamin D metabolism and regulation. Intact FGF 23 is biologically active. Author information: (1)Division of Pediatric Nephrology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California, USA. Enpp1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification and substrate for alkaline phosphatase, which converts it to Pi necessary for mineralization of bone. Hormonal FGF23 is produced by osteocytes and osteoblasts, although it is expressed elsewhere in disease.12. Despite the opposite effects on serum phosphorus concentration, the FGF23 mutant and FGF23/NaPi IIa mutant mice both developed decreased numbers of hypertrophic chondrocytes in the growth plate as well as a mineralization defect. FGF23 acts on the kidneys, where it decreases the expression of NPT2, a sodium-phosphate cotransporter in the proximal tubule. Several investigators have determined that FGF23 binds to various FGFRs [53,85,137,138]. FGF-23 inhibits surface expression of NPT2a and NPT2c in the proximal renal tubule, similarly to PTH, leading to decreased phosphate reabsorption. In early neonatal mineral metabolism, the role of FGF23, a novel regulator of P and vitamin D homeostasis, has not been evaluated. Jessica Kendrick MD, MPH, ... Sharon Moe MD, in Chronic Kidney Disease, Dialysis, and Transplantation (Fourth Edition), 2019. measured FGF23 mRNA in the calvaria of mice fed a diet containing 0.02% or 1% phosphate. In addition, FGF23 mRNA abundance was 30-fold higher in Hyp mouse calvaria, a condition known to be associated with elevated serum FGF23 concentrations. Fibroblast growth factor (FGF) 23, a member of the FGF19 subfamily of FGFs, plays a key role in balancing mineral ion homeostasis and bone mineralisation. In humans, 23 members of the FGF family have been identified, all of which are structurally related signaling molecules:. By 5 days of life, the iFGF23 was increased to near adult concentration, and cFGF23 was twice adult values at cord blood and at 5 days of life. Ces facteurs sont généralement sécrétés par des fibroblastes. Emerging evidence indicates that subtilisin-like protein convertase 2 (PC2) enzyme activity is decreased in the presence of PHEX deficiency due to decreased amounts of a chaperone protein necessary for PC2 activity. In addition to FGF23, there are other phosphatonins, such as matrix extracellular phosphoglycoprotein (MEPE), that may provide an intestine-kidney link. compared the phenotype of FGF23 mutant mice to FGF23/NaPi IIa double mutant and NaPi IIa mutant mice [142]. Chronic high levels of FGF23 are associated with left ventricular hypertrophy and mortality in patients with chronic kidney disease 6 and may also contribute to vascular calcification 7 , 8 . FGF-23 glycosylation by polypeptide N-acetylgalactosaminyltransferase 3 (GalNac-T3) decreases its susceptibility to cleavage and is necessary for adequate secretion of intact FGF-23. Bone turnover also regulates FGF-23 production through mechanisms that are not clear. Conversely PTH receptor activation stimulates osteocyte production of FGF-23. α-Klotho, bone, cardiovascular, fibroblast growth factor 23, fibroblast growth factor receptors, hypophosphatemia, innate immunity, kidney Search for Similar Articles You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. It is clear that humans and mice with elevated serum FGF23 levels develop hypophosphatemic disorders such as XLH, ADHR, and TIO that are characterized by rickets or osteomalacia. There is controversy regarding the location of action for FGF-23 receptors. The ability of Dmp1 to bind to integrins through the RGD motif and Phex through ASARM motif provides a molecular basis for Phex–Dmp1 interactions for regulating mineralization and FGF-23 production. 11.2). Sitara et al. Small, short-term studies have failed to show changes in FGF-23 levels based on changes in dietary phosphate. [8], FGF23 may also suppress 1-alpha-hydroxylase, reducing its ability to activate vitamin D and subsequently impairing calcium absorption. FGF23 levels strongly associate with clinical outcomes of CKD,64 especially with the intermediate surrogate, left ventricular hypertrophy.65 Extremely high FGF23 levels in CKD cause cardiac myocyte hypertrophy independent of klotho co-receptor function.66 FGF23 represents direct bone–kidney, bone–parathyroid and bone–heart connections in the systems biology involved in the CKD-MBD. Klotho is primarily expressed in the distal convoluted tubule (DCT), and some studies indicate that FGF-23 signaling begins in the distal tubule. The comparative analysis of the Hyp mouse homologue of XLH and dentin matrix acidic phosphoprotein 1 (Dmp1)-null mice further established a link between defects in extracellular matrix mineralization and FGF-23 expression. Brown, Mohammed S. Razzaque, in Textbook of Nephro-Endocrinology (Second Edition), 2018, FGF23, produced by osteocytes and osteoblasts of bone, is a recently discovered regulatory factor in phosphorus homeostasis.65–69 Renal phosphate wasting is caused by excessive levels of FGF23 in the serum, and the discovery of FGF23’s phosphate regulatory function was made after finding that autosomal-dominant hypophosphatemic rickets (ADHR) was caused genetically by mutations in the FGF23 gene. The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Over the past decade it has come clear that a disturbed calcium-phosphate metabolism, with Fibroblast Growth Factor-23 as a key hormone, is partly accountable for this enhanced risk. Figure 13.10. Following secretion this protein is inactivated by cleavage into a N-terminal fragment and a C-terminal … Elevations in FGF-23 are also observed in tumor-induced osteomalacia and as a paraneoplastic complication of certain prostate cancers that produce FGF-23 [55,56]. Members FGF1 through FGF10 all bind fibroblast growth factor receptors (FGFRs). This was confirmed in an osteoblast cell line. FGF23 contributes to maintainance of phosphate homeostasis during early CKD and causes vitamin D deficiency through increased catabolism. Perwad et al. FGFR1 plays a more important role in mediating the proximal tubular phosphaturic actions and distal tubular sodium and calcium reabsorption effects of FGF-23, whereas FGFR3 and 4 play a more important role in regulation of 1,25(OH)2D in the proximal tubule [63,64]. Fibroblast growth factor 23: are we ready to use it in clinical practice? Increases in calcitriol levels result in increases in FGF-23. The inactivation of this Enpp1 reduces the ratio of PPi to Pi, leading to increased mineralization of soft tissues as well as phosphate deficiency at the site of bone mineralization. The parathyroid glands express klotho, and cell culture data indicate that FGF-23 treatment suppresses PTH production. FGF23 is also overproduced by some types of tumors, such as the benign mesenchymal neoplasm Phosphaturic mesenchymal tumor causing tumor-induced osteomalacia, a paraneoplastic syndrome. This gene was identified by its mutations associated with autosomal dominant hypophosphatemic rickets. FGF23: Fibroblast growth factor 23 . Jessica Houston, ... Myles Wolf, in Nutritional Management of Renal Disease, 2013. [6][9], FGF23 is located on chromosome 12 and is composed of three exons. Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. Limb shortening has also been reported in FGF23-null mice [140]. Although these observations suggest that FGF23 plays an important role in skeletogenesis, conclusive data are lacking. Fibroblast growth factor 23 N-terminal peptide Add BLAST: 155: Chain i PRO_0000352876: 180 – 251: Fibroblast growth factor 23 C-terminal peptide Add BLAST: 72: Amino acid modifications. Recent studies indicate that FGF-23 is increased in callus during fracture healing, consistent with local matrix-derived FGF-23 stimulating factors [74]. Clinically, it is important to understand why there are associations between FGF23 and various adverse events, and what happens if we can decrease FGF23 levels and suppress FGF23 activity especially in patients with CKD. FGF 23 (Fibroblast Growth Factor 23) - FGF 23 is a major regulator of phosphate homeostasis. Parathyroid hormone (PTH) action at the PTH receptor (PTHR) inhibits apical expression of NPT2a and NPT2c, and stimulates expression of 1α-hydroxylase to increase 1,25(OH)2D. In chronic kidney disease (CKD), where biochemical evidence of mineral disturbances is especially common, FGF23 measurement has been advocated as an early and sensitive marker for CKD-related bone disease. Thus, FGF23 provides the key PTH-bone link and kidney-bone link. Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). Fibroblast growth factor 23: fueling the fire. Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone which is secreted by osteocytes and osteoblasts. However, the canonical effects of FGF-23 occur in the proximal renal tubule (Fig. In humans, high dietary phosphorus increases and low dietary phosphorus decreases serum FGF-23 [78–80]; but the changes are small, and there is a delay between phosphate loading and elevations of FGF-23 [80,81]. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). However, it is not clear whether these changes are due to altered phosphorus and vitamin D metabolism or if there is a direct effect of FGF23 on bone. An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. FGF-23 is a glycosylated peptide hormone produced primarily in osteocytes. facteur 23 de croissance du fibroblaste Caractéristiques générales; Nom approuvé FGF23 est une protéine appartenant à la famille des facteurs de croissances des fibroblastes (« fibroblast growth factor 23 »). This putative protein was known as phosphatonin. Chevetz et al. The ribs and vertebra of the FGF23-null mice demonstrate a marked increase in woven bone and osteoid. Limited data suggest that other hormones may also interact with FGF-23. By continuing you agree to the use of cookies. FGF-23 levels steadily rise in response to declining kidney function and can reach up to 1000-fold above the normal range by the time patients reach end stage renal disease (ESRD) [55]. Recombinant human FGF-23 is a 25.5kDa … For example, the detailed mechanisms of the regulation of FGF23 production remain largely unknown. Fibroblast growth factor 23 is a phosphatonin, which is a group of proteins that were identified from the study of genetic disorders characterized by hypophosphatemia due to urinary phosphate wasting, and from cases of tumor-induced osteomalacia associated with urinary phosphate wasting. While FGF-23 levels in dialysis patients directly correlate with serum phosphate levels [56,57] and with use of activated vitamin D [58], some have attributed the marked elevation of FGF-23 levels in CKD to decreased renal clearance of FGF-23 fragments [59]. Recent studies show that high molecular weight FGF2 (HMW-FGF2) and activation of both cell surface and intracrine FGFR1 signaling pathways stimulate FGF-23 in osteoblasts of Hyp mice. The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys. The ability of phosphate to regulate FGF-23, analogous to calcium regulation of PTH, has not been established, and neither a phosphate sensor nor predicable changes in FGF-23 in response to changes in serum phosphate occurs. Conditions of decreased FGF-23 function, either due to increased cleavage of FGF-23 into inactive fragments [due to mutations in GALNT3 (encoding polypeptide N-acetylgalactosaminyltransferase 3 (GalNac-T3) or FGF23], or insufficient FGF-23 activity (due to mutations in the coreceptor Klotho or to kidney disease) cause hyperphosphatemia and result in ectopic soft tissue and vascular calcifications. A member of the FGF19 subfamily, the FGF23 peptide in humans contains 251 amino acids, which is cleaved proteolytically during the secretion process. Bone histomorphometry reveals a mineralization defect with widened osteoid seams. Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. Its net effect is reduction in serum P and 1,25(OH)2D, which may result in hypocalcemia. This process is blocked by a MAPK inhibitor. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25‐dihydroxyvitamin D3 production. It is mainly produced in bone and also in the thymus and brain. 5.2).44. The cleavage site is located at positions 179 to 180 in the string of building blocks (amino acids) that make up the protein. There is growing interest in the role of fibroblast growth factor 23 (FGF23) in various diseases of disordered mineral metabolism. Seiji Fukumoto, in Translational Endocrinology of Bone, 2013. Studies in ovariectomized mice with chronic kidney disease indicate that restoring estrogen levels increases FGF-23 expression. IFG23 : Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate (phosphorus) homeostasis. FGF-23 also is a regulator of PTH. In healthy adults, Burnett-Bowie et al.136 found that PTH infusion increased FGF-23 over 18 hours, whereas Gutierrez et al.137 found that PTH infusion over 6 hours lowered FGF-23. 2011; 32:2688–2696. FGF-23 is also regulated by calcitriol. Indeed, inactivation of Phex leads to an intrinsic mineralization defect as well as increased FGF-23 expression in osteocytes [66–68]. Ronald B. Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene. Ablation of Dmp1, an extracellular matrix SIBLING protein that regulates mineralization, markedly stimulates the transcription of FGF-23 by osteocytes in mice, leading to the discovery that ARHR is caused by inactivating mutations of DMP1 [62]. A mechanism whereby bone mineralization regulates systemic phosphate homeostasis through FGF-23 has been suggested through the study of inactivating mutations of PHEX that lead to intrinsic abnormalities of mineralization and FGF-23-dependent hypophosphatemia [28,30,65]. Fibroblast growth factor 23 or FGF23 is a protein that in humans is encoded by the FGF23 gene. Dietary phosphate loading (i.e., 1.6%–2% phosphate diet) in mouse models of chronic kidney disease (CKD) result in significant elevations in serum FGF-23 [76], but severe dietary phosphate restriction failed to lower FGF-23 in another model of CKD [77]. Conditional deletion of Phex in the osteoblast lineage in vivo is sufficient to reproduce the Hyp phenotype, confirming that an intrinsic defect in bone leads to increased FGF-23 [69]. In addition, we do not know how FGF23 actually works. Elevated FGF23 concentrations are most often associated with increased phosphaturia and are seen in a number of hereditary hypophosphatemic forms of rickets; increased levels are also described in a number of other disorders.43,44 The role of FGF23 in early life remains to be established. X-linked hypophosphatemia and autosomal recessive hypophosphatemia). FGF23 directly inhibits the conversion of 25(OH)D to 1,25(OH)2D through downregulation of the CP27B1 in the kidney. However, longer studies show that dietary phosphate does modulate FGF-23 levels. FGF-23 inhibits parathyroid function and increases the parathyroid expression of the CaSR and vitamin D receptor making the gland more sensitive to the inhibitory actions of calcium and calcitriol. Thus, FGF-23 decreases both serum phosphate and 1,25(OH)2D concentrations. 10,14 The factors regulating FGF-23 production are incompletely understood; however, studies support that increased dietary phosphate intake stimulates FGF-23 production and that a negative feedback loop exists between FGF-23 and calcitriol. Effects of high phosphate diets on FGF-23 may be due to the effects of phosphate to chelate calcium leading to stimulation of PTH and 1,25(OH)2D levels or from proinflammatory responses related to calcium and phosphate crystals. Families. FGF23 is secreted primarily by bone, followed by thymus, heart, brain and, in low levels, by several other tissues. It is part of the atypical FGF subfamily. demonstrated that FGF23 binds to and activates the c-splice isoforms of FGFR 1-3 and FGFR4 [138]. While the cFGF23 is elevated in both cord blood and at 5 days,48 preterms maintained iFGF23 levels that were twice adult concentrations, and cFGF23 remained 10 times higher. FGF23 is a member of the fibroblast growth factor (FGF) family which participates in phosphate and vitamin D metabolism and regulation. Tube EDTA (bouchon lavande) Requête. Planned clinical trials to test the effects of phosphate binders on FGF-23 are also likely to lead to disappointing results [85], because FGF-23’s principal function is to regulate vitamin D metabolism, just as PTH’s major function is to regulate serum calcium, with both having secondary effects to regulate serum phosphate concentrations. FGF-23 is 251-amino acid protein synthesized by osteocytes and osteoblasts and is a major regulator of phosphate homeostasis. Hypophosphatemia caused by primary renal phosphate wasting in SLC34A1 (sodium-phosphate cotransporter 2a)-knockout mice is associated with low serum FGF-23, in spite of high serum 1,25(OH)2D and hypercalcemia [82,83]. Similarly, FGF23 can also suppress the renal expression of 1α(OH)ase to reduce production of 1,25(OH)2D3 to decrease intestinal phosphate absorption, resulting in reduced serum levels of phosphate.19,132. Keith A. Hruska, ... Kameswaran Surendran, in Chronic Renal Disease, 2015, FGF23 is the original phosphatonin (phosphate excretion regulating hormone) discovered in studies of autosomal dominant hypophosphatemic rickets and oncogenic osteomalacia.61,62 The principal hormonal functions identified for FGF23 are regulation of proximal tubular phosphate reabsorption, inhibition of CYP27B1, the 1α-hydroxylase synthesizing calcitriol in the proximal tubule, and stimulating the 25-hydroxyvitamin D3 24R-hydroxylase, 24-(OH) hydroxylase, CYP24A1. 21 This early decrease in circulating klotho downregulates the klotho‐FGF receptor complexes in the parathyroid gland so that PTH synthesis is no longer adequately suppressed. 2005; 90: 1519–1524. FGF23 was cloned in 2000 and has been established as a hormone regulating phosphate and vitamin D metabolism since then. a.bouma@amsterdamumc.nl. Fibroblast growth factor 23 also has an inhibitory effect on PTH production (Figure 48-1). Dynamic interplay of fibroblast growth factor‐23–αKlotho axis. Basolateral phosphate transport is not well understood. Laboratoire Central: Critère de rejet: Hémolyse 3+ Quantité requise pour fin d'analyse >1 mL: Source: Sang total: Contenant 1. FGF23 levels are stimulated by mild renal injury23,63 and progressively rise during the course of CKD due to increased secretion by osteocytes and decreased catabolism by the diseased kidney. FGF23 has been shown to be expressed in a number of tissues including bone. 31.2). 1,2,3,4 … Ce sont des protéines qui activent la migration et la multiplication de cellules cibles. Les facteurs de croissance des fibroblastes (ou FGF, sigle anglais de fibroblast growth factor) forment une famille comportant 23 protéines identifiées à ce jour chez l'homme (FGF1, FGF2... FGF23) . Bone is a buffer for calcium and phosphate and can release calcium and phosphate into the circulation in high bone remodeling states. In the setting of chronic kidney disease, parathyroid gland klotho expression decreases, and the response of the uremic parathyroid gland to FGF-23 declines. Klotho is primarily expressed in the distal convoluted tubule, and some studies indicate that FGF-23 signaling begins in the distal tubule. A physiological function of FGF-23 is to respond to changes in bone mineralization and turnover to adjust renal phosphate handling to balance the phosphate flux from bone. FGF23 is part of the newly recognized endocrine bone–parathyroid–kidney axis modulated by PTH, 1,25(OH)2D, and dietary and serum P levels.46 Synthesis and secretion of FGF23 by osteocytes are upregulated by increased serum 1,25(OH)2D and serum P and downregulated by P-regulating gene homologies to endopeptidases on the X chromosome (PHEX) and dentin matrix protein 1 (DMP1). [12] Mice lacking either FGF23 or the klotho enzyme display premature aging due to hyperphosphatemia.[13]. Yu et al. The mechanism by which calcitriol regulates FGF-23 is presumed to be via the vitamin D receptor. Diseases resulting in increased FGF-23 production result in hypophosphatemia due to excessive renal phosphate losses and cause osteomalacia and rickets. Numerous studies have been performed unravelling FGF23s actions and its association with … Ferrari SL, Bonjour J-P, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. Fibroblast growth factor 23 is normally cut (cleaved) at a certain site, which turns off (inactivates) the protein. In chronic kidney disease (CKD), where biochemical evidence of mineral disturbances is especially common, FGF23 measurement has been advocated as an early and sensitive marker for CKD-related bone disease. FGF-23 regulates renal phosphate transport and loss of FGF-23 leads to hyperphosphatemia. Osteocytes and osteoblasts of normal bone express FGF23 and is likely the primary source of circulating FGF23 [76,119]. The NaPi IIa mutant mice did not develop these findings suggesting that the bone phenotype that develops due to FGF23 abnormalities are not entirely due to changes in serum phosphate metabolism and FGF23 likely has a direct effect in bone. This cleavage helps regulate the amount of active fibroblast growth factor 23 circulating in the bloodstream. The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. Intact FGF-23 interacts with FGFR-1, FGFR-3, and FGFR-4, requiring klotho as a critical coreceptor. Copyright © 2021 Elsevier B.V. or its licensors or contributors. Mutations in FGFR3 result in achondroplasia, hypochondroplasia, or thanantophoric dysplasia, which are characterized by various degrees of limb deformity including shortening and bowing. Whether FGF-23 is regulated by dietary phosphate is unclear. L. Darryl Quarles, in Vitamin D (Fourth Edition), 2018. Linda A. DiMeglio, Erik A. Imel, in Basic and Applied Bone Biology, 2014.