Role of fibroblast growth factor 23 in health and in chronic kidney disease

Purpose of reviewThis review summarizes the molecular properties and biological roles of a new phosphaturic factor, fibroblast growth factor 23 (FGF23). Significant roles of FGF23 are discussed, especially in terms of its effects on the kidney, the main target organ. Recent findingsFGF 23 is a recently discovered phosphaturic factor. Several animal experiments including overexpression or ablation of the FGF23 gene have recently revealed the significant effects of this factor on phosphate excretion and on vitamin D synthesis in the kidney. Although FGF23 was originally identified as a factor responsible for several hypophosphatemic disorders, recent data indicate its role in the physiological regulation of phosphate homeostasis. In chronic kidney disease, FGF23 plays a crucial role in the pathogenesis of secondary hyperparathyroidism. Effects of FGF23 on other organs including bone and intestine remain to be elucidated. SummaryFGF23 is a physiological regulator of phosphate homeostasis. Excessive activity of FGF23 with normal renal function results in hypophosphatemia, low 1,25-dihydroxyvitamin D levels, and rickets/osteomalacia. By contrast, excessive FGF23 activity suppresses 1,25-dihydroxyvitamin D synthesis, but may not be sufficient to excrete the phosphate load appropriately with deteriorating renal function, both of which contribute to the development of hyperparathyroidism.

[1]  S. Fukumoto,et al.  Intravenous Calcitriol Therapy Increases Serum Concentrations of Fibroblast Growth Factor-23 in Dialysis Patients with Secondary Hyperparathyroidism , 2005, Nephron Clinical Practice.

[2]  B. Deyoung,et al.  Elevated fibroblast growth factor‐23 in hypophosphatemic linear nevus sebaceous syndrome , 2005, American journal of medical genetics. Part A.

[3]  A. Delezoide,et al.  Expression of fibroblast growth factors 18 and 23 during human embryonic and fetal development. , 2005, Gene expression patterns : GEP.

[4]  I. Narita,et al.  Pretreatment serum FGF-23 levels predict the efficacy of calcitriol therapy in dialysis patients. , 2005, Kidney international.

[5]  T. Shigematsu,et al.  Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. , 2005, Kidney international.

[6]  R. Rizzoli,et al.  Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. , 2005, The Journal of clinical endocrinology and metabolism.

[7]  K. White,et al.  Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. , 2005, American journal of human genetics.

[8]  P. Orlik,et al.  An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. , 2005, Human molecular genetics.

[9]  S. Kato,et al.  Circulating FGF-23 Is Regulated by 1α,25-Dihydroxyvitamin D3 and Phosphorus in Vivo* , 2005, Journal of Biological Chemistry.

[10]  K. Miyamoto,et al.  Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells. , 2005, American journal of physiology. Endocrinology and metabolism.

[11]  M. Razzaque,et al.  Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. , 2004, Matrix biology : journal of the International Society for Matrix Biology.

[12]  R. Mason,et al.  Bone as a source of FGF23: regulation by phosphate? , 2004, Bone.

[13]  D. Miao,et al.  Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. , 2004, Endocrinology.

[14]  M. Econs,et al.  FGF-23 is elevated by chronic hyperphosphatemia. , 2004, The Journal of clinical endocrinology and metabolism.

[15]  N. Goto,et al.  Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[16]  Kozo Nakamura,et al.  Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. , 2004, The Journal of clinical endocrinology and metabolism.

[17]  T. Shigematsu,et al.  Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[18]  T. Strom,et al.  FGF23 is processed by proprotein convertases but not by PHEX. , 2004, Bone.

[19]  T. Shigematsu,et al.  Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. , 2004, European journal of endocrinology.

[20]  C. Ohlsson,et al.  Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. , 2004, Endocrinology.

[21]  M. Inaba,et al.  FGF-23 in patients with end-stage renal disease on hemodialysis. , 2004, Kidney international.

[22]  S. Kato,et al.  Intestinal Na-P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. , 2004, American journal of physiology. Renal physiology.

[23]  Y. Takeuchi,et al.  Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. , 2004, The Journal of clinical investigation.

[24]  T. Yoneya,et al.  FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. , 2004, Biochemical and biophysical research communications.

[25]  Y. Takeuchi,et al.  FGF‐23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  H. Jüppner,et al.  Circulating concentration of FGF-23 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. , 2003, Kidney international.

[27]  H. Murer,et al.  Regulation of Na/Pi transporter in the proximal tubule. , 2003, Annual review of physiology.

[28]  L. Quarles,et al.  Regulation of Fibroblastic Growth Factor 23 Expression but Not Degradation by PHEX* , 2003, Journal of Biological Chemistry.

[29]  K. White,et al.  FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. , 2003, The Journal of clinical investigation.

[30]  S. Fukumoto,et al.  Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. , 2003, The New England journal of medicine.

[31]  K. Miyamoto,et al.  Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter , 2003, Pflügers Archiv.

[32]  L. Quarles,et al.  Serum FGF23 Levels in Normal and Disordered Phosphorus Homeostasis , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[33]  D. Miao,et al.  The Autosomal Dominant Hypophosphatemic Rickets R176Q Mutation in Fibroblast Growth Factor 23 Resists Proteolytic Cleavage and Enhances in Vivo Biological Potency* , 2003, The Journal of Biological Chemistry.

[34]  K. Miyamoto,et al.  Human Fibroblast Growth Factor-23 Mutants Suppress Na+-dependent Phosphate Co-transport Activity and 1α,25-Dihydroxyvitamin D3 Production* , 2003, The Journal of Biological Chemistry.

[35]  Y. Takeuchi,et al.  Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. , 2002, The Journal of clinical endocrinology and metabolism.

[36]  Nobuyuki Itoh,et al.  Fibroblast Growth Factor (FGF)-23 Inhibits Renal Phosphate Reabsorption by Activation of the Mitogen-activated Protein Kinase Pathway* , 2002, The Journal of Biological Chemistry.

[37]  T. Yoneya,et al.  Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. , 2002, Endocrinology.

[38]  R. Kumar,et al.  Tumors Associated With Oncogenic Osteomalacia Express Genes Important in Bone and Mineral Metabolism , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  T. Strom,et al.  Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. , 2001, Kidney international.

[40]  L. Quarles,et al.  Analysis of recombinant Phex: an endopeptidase in search of a substrate. , 2001, American journal of physiology. Endocrinology and metabolism.

[41]  J. Bertram,et al.  Fibroblast growth factor receptors and their ligands in the adult rat kidney. , 2001, Kidney international.

[42]  R. Kumar,et al.  FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. , 2001, Biochemical and biophysical research communications.

[43]  S. Takeda,et al.  Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  T. Meitinger,et al.  Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 , 2000, Nature Genetics.

[45]  N. Itoh,et al.  Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. , 2000, Biochemical and biophysical research communications.

[46]  A. Poustka,et al.  A gene (PEX) with homologies to endopeptidases is mutated in patients with X–linked hypophosphatemic rickets , 1995, Nature Genetics.

[47]  Y. Takeuchi,et al.  Targeted ablation of Fgf 23 demonstrates an essential physiological role of FGF 23 in phosphate and vitamin D metabolism , 2004 .

[48]  R. Kumar,et al.  The phosphatonin pathway: new insights in phosphate homeostasis. , 2004, Kidney international.

[49]  K. White,et al.  Renal phosphate wasting disorders: clinical features and pathogenesis. , 2004, Seminars in nephrology.

[50]  L. Quarles,et al.  REGULATION OF FGF 23 EXPRESSION BUT NOT DEGRADATION BY PHEX , 2003 .