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.
"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  . DMP1 was proposed to act as a transcription factor  and MEPE is probably involved in regulating FGF23 indirectly, by inhibiting PHEX . 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  . "
"Fibroblast growth factor 23 (FGF23) is a 251-amino-acid protein secreted by osteocytes in adults
, and it is an important regulator that maintains serum phosphorus levels within the normal range in patients with CKD by increasing urinary phosphate excretion and decreasing dietary phosphorus absorption through the inhibition of 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis
. In patients with CKD, FGF23 levels are thought to increase as an appropriate compensatory mechanism to maintain a normal phosphate balance, in parallel with a declining capacity for renal phosphate excretion
[Show abstract][Hide abstract] ABSTRACT: Background
Fibroblast growth factor 23 (FGF23) is an important hormone in the regulation of phosphate metabolism. It is unclear whether FGF23 is associated with carotid artery calcification (CAAC) in predialysis patients. The present study aimed to clarify the relationship between FGF23 and CAAC in patients with chronic kidney disease (CKD) who were not on dialysis.
One-hundred ninety-five predialysis CKD patients were enrolled in this cross-sectional study. CAAC was assessed using multidetector computed tomography, and the prevalence of CAAC was examined. Intact FGF23 was measured in each patient. The risk factors for CAAC were evaluated using a logistic regression model.
We found CAAC in 66% of the patients. The prevalence of CAAC significantly increased across CKD stages: it was 37% in CKD stages 1–2, 58% in stage 3; 75% in stage 4, and 77% in stage 5 (p < 0.01). In multivariate analysis, smoking, diabetes mellitus and log FGF23 were each identified as risk factors for CAAC. The study population was divided in quartiles of FGF23 levels. Compared with the lowest FGF23 quartile, each subsequent quartile had a progressively higher odds ratio (OR) for CAAC, adjusted for confounders (ORs [95% confidence interval] of 2.34 [0.78 to 7.31], 5.28 [1.56 to 19.5], and 13.6 [2.92 to 74.6] for the second, third, and fourth quartiles, respectively.
The prevalence of CAAC is increased with the decline in the kidney function. FGF23 is independently related to CAAC in patients with CKD who are not on dialysis.
"FGF23 is a bone-derived hormone that regulates phosphate and vitamin D metabolism through FGFR/α-Klotho co-receptors  that are expressed in a limited number of tissues, including the kidney . In the kidney, FGF23 suppresses sodium-phosphate co-transporter function leading to phosphaturia and reduces 1,25(OH)2D synthesis in the proximal tubule , . Physiologically, FGF23 is part of a bone-kidney feedback loop , , where circulating 1,25(OH)2D stimulates FGF23 production in bone and FGF23 suppresses 1,25(OH)2D production in the kidney . "
[Show abstract][Hide abstract] ABSTRACT: Elevations of circulating Fibroblast growth factor 23 (FGF23) are associated with adverse cardiovascular outcomes and progression of renal failure in chronic kidney disease (CKD). Efforts to identify gene products whose transcription is directly regulated by FGF23 stimulation of fibroblast growth factor receptors (FGFR)/α-Klotho complexes in the kidney is confounded by both systemic alterations in calcium, phosphorus and vitamin D metabolism and intrinsic alterations caused by the underlying renal pathology in CKD. To identify FGF23 responsive genes in the kidney that might explain the association between FGF23 and adverse outcomes in CKD, we performed comparative genome wide analysis of gene expression profiles in the kidney of the Collagen 4 alpha 3 null mice (Col4a3(-/-)) model of progressive kidney disease with kidney expression profiles of Hypophosphatemic (Hyp) and FGF23 transgenic mouse models of elevated FGF23. The different complement of potentially confounding factors in these models allowed us to identify genes that are directly targeted by FGF23. This analysis found that α-Klotho, an anti-aging hormone and FGF23 co-receptor, was decreased by FGF23. We also identified additional FGF23-responsive transcripts and activation of networks associated with renal damage and chronic inflammation, including lipocalin 2 (Lcn2), transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) signaling pathways. Finally, we found that FGF23 suppresses angiotensin-converting enzyme 2 (ACE2) expression in the kidney, thereby providing a pathway for FGF23 regulation of the renin-angiotensin system. These gene products provide a possible mechanistic links between elevated FGF23 and pathways responsible for renal failure progression and cardiovascular diseases.
PLoS ONE 09/2012; 7(9):e44161. DOI:10.1371/journal.pone.0044161 · 3.23 Impact Factor
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