Disease relevance of Fgf23

• Regardless, the deletion of Fgf23 from Hyp mice reversed the hypophosphatemia, abnormal 1,25(OH)(2)D(3) levels, rickets, and osteomalacia associated with Phex deficiency [1].
• In summary, Fgf23 is suppressed in diet-induced hypophosphatemia and in hypophosphatemia associated with secondary hyperparathyroidism [2].
• To genetically separate the effects of phosphate and vitamin D on Fgf23, we examined vitamin D receptor null (VDR(-/-)) mice, which are hypocalcemic and hypophosphatemic secondary to hyperparathyroidism [2].
• Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets [3].
• Reciprocally tumoral calcinosis (TC) patients are often hyperphosphatemic with inappropriately normal or elevated serum 1,25(OH)2D3 levels and have ectopic and vascular calcifications, a phenotype similar to that of Fgf23 null mice [4].

High impact information on Fgf23

• Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria [5].
• Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts [6].
• Disruption of the Fgf23 gene did not result in embryonic lethality, although homozygous mice showed severe growth retardation with abnormal bone phenotype and markedly short life span [7].
• These phenotypes could not be explained by currently known regulators of mineral homeostasis, indicating that FGF23 is essential for normal phosphate and vitamin D metabolism [7].
• We present here the evidence that FGF23 is a physiological regulator of serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D) by generating FGF23-null mice [7].

Chemical compound and disease context of Fgf23

• The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone [8].
• In FGF-23 knockout mice, 25-hydroxyvitamin D 1alpha-hydroxylase expression is increased and elevated serum 1alpha,25(OH)(2)D levels cause significant hypercalcemia and hyperphosphatemia [9].
• Patients and experimental animals with increased circulating levels of fibroblast growth factor 23 present with hypophosphataemia, increased urinary phosphate excretion, inappropriate calcitriol synthesis and rickets/osteomalacia, but no nephrolithiasis except when treated [10].

Biological context of Fgf23

• Fgf-23-/-) mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs [11].
• Inactivating mutations of the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) endopeptidase, the disease-causing gene in X-linked hypophosphatemia (XLH), results in increased circulating levels of fibroblastic growth factor-23 (FGF23), a bone-derived phosphaturic factor [1].
• To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene [11].
• The data suggest that genotype-dependent and dietary Pi-induced changes in the serum FGF-23 concentration reflect changes in fgf-23 gene expression in bone [12].
• Fibroblast growth factor-23 (FGF-23) has been recently identified as playing an important pathophysiological role in phosphate homeostasis and vitamin D metabolism [13].

Anatomical context of Fgf23

• Surprisingly, eGFP expression was not increased in cell surface osteoblasts, indicating that Phex deficiency is necessary but not sufficient for increased Fgf23 expression in the osteoblast lineage [1].
• Additional factors, associated with either osteocyte differentiation and/or extracellular matrix, are necessary for Phex deficiency to stimulate Fgf23 gene transcription in bone [1].
• Because mouse Fgf23 mRNA was expressed in dendritic cells and activated spleen, tumor infiltrating dendritic cells are candidate sources of FGF23 secretion in TIO patients [14].
• Therefore, we examined the mechanism of action of FGF-23 in cultured renal proximal epithelial cells, opossum kidney cells [15].
• Fgf-23 mRNA abundance in calvaria was significantly higher in Hyp mice than in WT mice on the 1% Pi diet; in both groups of mice, fgf-23 mRNA abundance in calvarial bone was suppressed by 85% on the low (0.02%) Pi diet [12].

Associations of Fgf23 with chemical compounds

• Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro [3].
• We conclude that FGF23 reduces renal Pi transport and 25-hydroxyvitamin D 1a-hydroxylase levels by a mechanism that is independent of the VDR [16].
• FGF-23 was found to require heparin-like molecules for its inhibitory activity on phosphate uptake [15].
• Inhibitors of the MAPK pathway, PD98059 and SB203580, also blocked the activity of FGF-23 [15].
• An inhibitor for tyrosine kinases of the FGF receptor, SU 5402, blocked the activity of FGF-23 [15].

Physical interactions of Fgf23

• FGF-23 binds to the FGF receptor 3c, which is mainly expressed in opossum kidney cells, with high affinity [15].

Regulatory relationships of Fgf23

• CONCLUSIONS: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism [17].

Other interactions of Fgf23

• The authors found that Hyp mice had increased expression of the MEPE and another phosphaturic factor, Fgf23 [18].
• Normalization of serum phosphate by diet in VDR(-/-) mice increases Fgf23 [2].
• In Npt2a(-/-) mice, serum FGF-23 concentrations were significantly lower than in WT mice, and these differences could be accounted for by the lower serum Pi levels in Npt2a(-/-) mice [12].
• Finally, our data support a new model of interactions among Fgf-23, vitamin D, and klotho, a gene described as being associated with premature aging process [19].
• FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h [17].

Analytical, diagnostic and therapeutic context of Fgf23

• Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations [2].
• In contrast, by real-time reverse transcriptase PCR, the levels of fgf23 transcripts were highest in bone, the predominant site of Phex expression [20].
• In osteoblast cell cultures, 1,25(OH)(2)D(3) but not calcium, phosphate, or parathyroid hormone stimulated FGF23 mRNA levels and resulted in a dose-dependent increase in FGF23 promoter activity [21].
• The localization of FGF-23 mRNA in the brain was examined by in situ hybridization [22].
• Western blot analysis using site-specific antibodies showed that wild-type FGF-23 secreted into conditioned media was partially cleaved between Arg(179) and Ser(180) [23].

References