File Name: regulation of phosphate homeostasis by pth vitamin d and fgf23 .zip
- Disorders of Calcium and Phosphorus Metabolism and the Proteomics/Metabolomics-Based Research
- Regulation of Phosphate Homeostasis by PTH, Vitamin D, and FGF23
- Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)
- Clinical Significance of FGF-23 in Patients with CKD
Since calcium and phosphorus play vital roles in a multitude of physiologic systems, disorders of calcium and phosphorus metabolism always lead to severe consequences such as skeletal-related and cardiovascular morbidity, or even life-threatening. Physiologically, the maintenance of calcium and phosphorus homeostasis is achieved via a variety of concerted actions of hormones such as parathyroid hormone PTH , vitamin D, and fibroblast growth factor FGF23 , which could be regulated mainly at three organs, the intestine, kidney, and bone. Disruption of any organ or factor might lead to disorders of calcium and phosphorus metabolism.
Disorders of Calcium and Phosphorus Metabolism and the Proteomics/Metabolomics-Based Research
Facultad de Veterinaria. The regulation of mineral metabolism is achieved trough a complex interaction of hormonal factors and target organs. Before the discovery of FGF23 we believed that the regulation of serum calcium and phosphate was mainly the result of changes in PTH and vitamin D acting on bone, kidneys and intestine.
Presently we know that FGF23 is produced by bone so the bone is not longer just a target organ but an active endocrine organ that participate in the regulation of mineral metabolism by sending signals through FGF Nephrologists are knowledgeable about the regulation of calcium and phosphate otherwise it is difficult to understand and manage the disturbances of mineral metabolism that are always present in patients with CKD.
The regulation of calcium and phosphate was only partially understood until the discovery of FGF Let's think in a situation of hypocalcemia; the parathyroids respond promptly to a decrease in serum calcium, elevated PTH acts on bone to increase the exit of calcium, but the calcium release from bone is also accompanied by the release of phosphate. The PTH acts also in kidneys increasing the tubular reabsorption of calcium so the calcium released by bone is kept in the extracellular space.
The PTH produces phosphaturia so the phosphate released by bone does not build up in the extracellular space. This may not be sufficient to bring the calcium up to normal, therefore the elevated PTH stimulatesrenal production of 1,25 OH 2D3 which in turn stimulates intestinal calcium absorption. This regulatory system appears to be adequate to control serum calcium, however 1,25 OH 2D3 not only increase gut absorption of calcium but also the absorption of phosphate.
It does not seem logical that a synchronized hormonal response to correct hypocalcemia had to be concluded with an excess of phosphate. Thus the presence of FGF23 enables the system to restore the serum calcium without the trouble of phosphate accumulation Figure 2.
Figure 1. Hormonal response to hypocalcemia. Ca: calcium; PTH: parathyroid hormone; P: phosphate. Figure 2. Hormonal response to hypocalcemia and the role of FGF23 to maintain phosphate balance. FGF23 is a kDa amino acid protein produced by osteocytes and osteoblasts which makes the bone an endocrine organ that communicates with other organs involved in mineral homeostasis. FGF23 acts on its receptor complex, klotho-FGFR1, in the kidney to cause phosphaturia and to decrease calcitriol synthesis.
FGF23 production by osteoblasts and osteocytes is stimulated by high dietary intake of phosphate however the mechanisms at the cellular level are unknown. Liu S et al.
Interestingly Carrillo et al. Parathyroid tissue expresses a significant amount of klotho 11 and FGF23 receptor. Thus it was reasonable to anticipate an effect of FGF23 on the parathyroids. In vivo and in vitro studies demonstrated that FGF23 increased gene expression and protein levels of both calcium sensing and Vitamin D receptors. Finally the same authors showed that FGF23 decreased parathyroid cell proliferation. All these results strongly suggest that FGF23 inhibits parathyroid function in normal parathyroids.
The expression of FGF23 receptor and klotho in parathyroids have been investigated. Some experiments have shown that administration of FGF23 produces upregulation of parathyroid klotho, 13 other authors 14 observed that FGF23 produced an increase in klotho that did not reach significance.
High extracellular calcium was able to increase in both parathyroid klotho and FGF receptor expression in normal parathyroid glands. FGF23 in patients with chronic kidney disease. The pathogenesis of secondary hyperparathyroidism. For many years accumulation of phosphate and vitamin D deficiency were considered the key factors in the development of secondary hyperparathyroidism.
The increased production of FGF23 in CKD patients is most likely due to the increase in body burden of phosphate not necessarily accompanied by hyperphosphatemia. FGF23 induces phosphaturia, which may explain why serum levels of phosphate are maintained in early stages of CKD. Progressive loss of nephrons will make both FGF23 and PTH non-operative and then serum phosphate concentration will increase.
Nephrologists frequently ask whether or not it is advantageous to have elevation of FGF Certainly FGF23 helps to control phosphate balance but contributes to vitamin D deficiency.
Furthermore recent experiments demonstrate a direct negative effect of FGF23 on the cardiovascular system. Therefore the increase in FGF23 implies inadequate phosphate control. FGF23 levels may not reflect acute changes in dietary phosphate; however high serum level of FGF23 may reveal a long period of positive phosphate balance.
Certainly, clinical studies will have to be performed to prove the usefulness of FGF23 as a marker of phosphate balance. A considerable amount of clinical studies have shown that a high FGF23 level is independent predictor of mortality, progression of renal disease 28,29 left ventricular hypertrophy, 30,31 vascular dysfunction, 32 renal transplant outcome 33 and experimental work have shown that FGF23 causes ventricular hypertrophy directly.
In dialysis patients serum FGF23 levels are markedly increased and they are positively correlated with serum PTH levels and with serum levels of phosphate. Experimental work in uremic rats with secondary hyperparathyroidism revealed that administration of FGF23 did not reduce serum levels of FGF23 in uremic rats; and, in vitro hyperplastic parathyroid glands from uremic rats did not respond to FGF Further experiments showed that hyperplastic parathyroid glands presented low expression of both FGF receptors and klotho.
This results suggests a resistance of hyperplastic parathyroid gland to the inhibitory action of FGF After renal transplant many patients maintain high FGF23 levels suggesting that FGF23 may be the cause of of post-transplant hypophosphatemia with a relative vitamin D deficiency. It is not clear why FGF23 secretion is maintained after transplantationdespite hypophosphatemia.
Kidney Int ;69 11 Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. FGF is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res ; Latest findings in phosphate homeostasis. Kidney Int ; Nature ; Role of hyperphosphatemia and 1,dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol ; Fibroblast growth factor relationship to dietary phosphate and renal phosphate handling in healthy young men.
J Clin Endocrinol Metab ; Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. Alpha-Klotho as a regulator of calcium homeostasis. Science ; The parathyroid is a target organ for FGF23 in rats. J Clin Invest ; Fibroblast growth factor regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells.
J Endocrinol ; FGF23 fails to inhibit uremic parathyroid glands. Circulating concentration of FGF increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers.
FGF in patients with end-stage renal disease on hemodialysis. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis ; Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease.
Isakova T, Wolf MS. Rodriguez M, Felsenfeld A. Nephrol Dial Transplant ;23 11 Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol ;19 3 FGF23 induces left ventricular hypertrophy. J Clin Invest ; 11 Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients.
Nephrol Dial Transplant ;26 8 Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med ; High levels of serum fibro- blast growth factor FGF are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant ; Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.
JAMA ; 23 J Am Soc Nephrol ;18 9 FGF as predictor of renal outcome in diabetic nephropaty. Clin J Am Soc Nephrol ;6 2 Fibroblast growth factor a possible cause of left ventricular hypertrophy in hemodialysis pa tients. Am J Med Sci ; Fibroblast growth factor and left ventricular hypertrophy in chronic kidney disease.
Circulation ; Circulating fibro-blast growth factor is associated with vascular dysfunction in the community. Atherosclerosis ;
Regulation of Phosphate Homeostasis by PTH, Vitamin D, and FGF23
Colin R. Dunstan, Hong Zhou, Markus J. Inorganic phosphate Pi is a critical circulating ion required to support multiple essential cellular processes dependent on phosphorus, including energy transport, nucleotide synthesis, and intracellular cell signaling. In addition, Pi is essential with calcium for the mineralization of bone matrix through the formation of hydroxyapatite crystals [Ca 10 PO 4 6 OH 2 ]. Normally, levels of Pi in the plasma are maintained in the range of approximately 2.
Studies of several renal phosphate wasting syndromes resulted in the identification of four factors with the predicted characteristics of phosphatonins, which are named as fibroblast growth factor 23 FGF23 , secreted frizzled related protein 4 SFRP4 , matrix extracellular phosphoglycoprotein MEPE , and FGF The FGF family consists of 22 members for various functions. FGF23 is a peptide released from bone tissue and osteogenic cells 1. It is represented as a hormone that acts in embryonic development, cellular differentiation, tissue repair, and tumor growth 6 , 7. Although FGF23 may affect kidney, parathyroid gland, and possibly the pituitary gland and choroid plexus, its major target tissue is kidney 8. FGF23 is shown to be phosphaturic.
Facultad de Veterinaria. The regulation of mineral metabolism is achieved trough a complex interaction of hormonal factors and target organs. Before the discovery of FGF23 we believed that the regulation of serum calcium and phosphate was mainly the result of changes in PTH and vitamin D acting on bone, kidneys and intestine. Presently we know that FGF23 is produced by bone so the bone is not longer just a target organ but an active endocrine organ that participate in the regulation of mineral metabolism by sending signals through FGF Nephrologists are knowledgeable about the regulation of calcium and phosphate otherwise it is difficult to understand and manage the disturbances of mineral metabolism that are always present in patients with CKD. The regulation of calcium and phosphate was only partially understood until the discovery of FGF
In turn, FGF23 inhibits the synthesis of 1,25(OH)(2)D, and it may negatively regulate the secretion of parathyroid hormone (PTH) from the.
Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)
The function of fibroblast growth factor FGF 23 has been suggested to be multifaceted beyond its canonical function as a regulator of mineral metabolism. FGF23 was originally shown to play a central role in phosphate Pi and vitamin D metabolism, and a number of diseases associated with dysregulated Pi metabolism have been attributed to abnormal FGF23 signaling activities. The discovery of Klotho as a co-receptor for FGF23 signaling has also accelerated understanding on the molecular mechanisms underlying Pi and vitamin D metabolism. In addition to these canonical functions, FGF23 has recently been implicated in a number of metabolic diseases including chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown. Molecular and functional insights into the FGF23 pathway will be discussed in the present review, with an emphasis on its role in human disorders related to dysregulated Pi metabolism as well as metabolic disorders.
In contrast to the regulation of calcium homeostasis, which has been extensively studied over the past several decades, relatively little is known about the regulation of phosphate homeostasis. Synthesis and secretion of FGF23 by osteocytes are positively regulated by 1,25 OH 2 D and serum phosphorus and negatively regulated, through yet unknown mechanisms, by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome PHEX and by dentin matrix protein 1 DMP1.
Clinical Significance of FGF-23 in Patients with CKD
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PTH, 1,25(OH)2-vitamin D, FGF23, phosphate homeostasis. Abstract. In contrast to the regulation of calcium homeostasis, which has been ex- tensively studied.
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