Regulation and function of the FGF23/klotho endocrine pathways

Physiological Reviews

Volumn 92, Issue 1, 2012, Pages 131-155

  Martin, Aline ^a   David, Valentin ^a   Darryl Quarles, L ^a  

^a UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,25 DIHYDROXYERGOCALCIFEROL; CALCITRIOL; CALCIUM; DENTIN MATRIX PROTEIN 1; FIBROBLAST GROWTH FACTOR 19; FIBROBLAST GROWTH FACTOR 21; FIBROBLAST GROWTH FACTOR 23; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FIBROBLAST GROWTH FACTOR RECEPTOR 2; FIBROBLAST GROWTH FACTOR RECEPTOR 3; FIBROBLAST GROWTH FACTOR RECEPTOR 4; GLUCOCORTICOID; IRON; KLOTHO PROTEIN; PARATHYROID HORMONE; PHOSPHATE; PHOSPHATE REGULATING NEUTRAL ENDOPEPTIDASE; PREDNISONE; VITAMIN D;

AUTOCRINE EFFECT; BONE; BONE DISEASE; BONE METABOLISM; BONE MINERALIZATION; BONE TURNOVER; BRAIN; CARDIOVASCULAR SYSTEM; CHRONIC KIDNEY DISEASE; GENETIC TRANSCRIPTION; HOMEOSTASIS; HUMAN; HYPERPARATHYROIDISM; HYPERPHOSPHATEMIA; HYPOCALCEMIA; HYPOPHOSPHATEMIA; INTESTINE ABSORPTION; KIDNEY; KIDNEY PROXIMAL TUBULE; KIDNEY TUBULE ABSORPTION; LYMPHOPOIESIS; NONHUMAN; ONCOGENIC OSTEOMALACIA; OSTEOBLAST; OSTEOCYTE; PARACRINE SIGNALING; PARATHYROID GLAND; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROCESSING; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; SKELETON; TISSUE SPECIFICITY; VITAMIN D METABOLISM; X CHROMOSOME;

ANIMALS; CALCIUM; ENDOCRINE SYSTEM; FIBROBLAST GROWTH FACTORS; GLUCURONIDASE; HOMEOSTASIS; HUMANS; PHOSPHATES; SIGNAL TRANSDUCTION;

EID: 84856720641     PISSN: 00319333     EISSN: 15221210     Source Type: Journal    
DOI: 10.1152/physrev.00002.2011     Document Type: Review

References (232)

1. Addison WN, Nakano Y, Loisel T, Crine P, McKee MD. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 23: 1638-1649, 2008.
2. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26: 345-348, 2000.
3. Aizawa H, Saito Y, Nakamura T, Inoue M, Imanari T, Ohyama Y, Matsumura Y, Masuda H, Oba S, Mise N, Kimura K, Hasegawa A, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R. Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats. Biochem Biophys Res Commun 249: 865-871, 1998.
4. Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol 3: 658-664, 2008.
5. Anamizu Y, Kawaguchi H, Seichi A, Yamaguchi S, Kawakami E, Kanda N, Matsubara S, Kuro-o M, Nabeshima Y, Nakamura K, Oyanagi K. Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells. Acta Neuropathol 109: 457-466, 2005.
6. Anderson HC, Harmey D, Camacho NP, Garimella R, Sipe JB, Tague S, Bi X, Johnson K, Terkeltaub R, Millan JL. Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleotide pyrophosphatase phosphodiesterase 1 double-deficient mice. Am J Pathol 166: 1711-1720, 2005.
7. Araya K, Fukumoto S, Backenroth R, Takeuchi Y, Nakayama K, Ito N, Yoshii N, Yamazaki Y, Yamashita T, Silver J, Igarashi T, Fujita T. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 90: 5523-5527, 2005.
8. Bai X, Miao D, Goltzman D, Karaplis AC. Early lethality in Hyp mice with targeted deletion of Pth gene. Endocrinology 148: 4974-4983, 2007.
9. Bai X, Miao D, Li J, Goltzman D, Karaplis AC. Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology 145: 5269-5279, 2004.
10. Bai XY, Miao D, Goltzman D, Karaplis AC. The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 278: 9843-9849, 2003.
11. Barbieri AM, Filopanti M, Bua G, Beck-Peccoz P. Two novel nonsense mutations in GALNT3 gene are responsible for familial tumoral calcinosis. J Hum Genet 52: 464-468, 2007.
12. Baum M, Schiavi S, Dwarakanath V, Quigley R. Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules. Kidney Int 68: 1148-1153, 2005.
13. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117: 4003-4008, 2007.
14. Bergwitz C, Banerjee S, Abu-Zahra H, Kaji H, Miyauchi A, Sugimoto T, Juppner H. Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis. J Clin Endocrinol Metab 94: 4267-4274, 2009.
15. Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun 284: 977-981, 2001.
16. Brown WW, Juppner H, Langman CB, Price H, Farrow EG, White KE, McCormick KL. Hypophosphatemia with elevations in serum fibroblast growth factor 23 in a child with Jansen's metaphyseal chondrodysplasia. J Clin Endocrinol Metab 94: 17-20, 2009.
17. Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP. A translocation causing increased alphaklotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci USA 105: 3455-3460, 2008.
18. Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 21: 1187-1196, 2006.
19. Campos M, Couture C, Hirata IY, Juliano MA, Loisel TP, Crine P, Juliano L, Boileau G, Carmona AK. Human recombinant endopeptidase PHEX has a strict S1' specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein. Biochem J 373: 271-279, 2003.
20. Canalejo R, Canalejo A, Martinez-Moreno JM, Rodriguez-Ortiz ME, Estepa JC, Mendoza FJ, Munoz-Castaneda JR, Shalhoub V, Almaden Y, Rodriguez M. FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol 21: 1125-1135, 2010.
21. Cancilla B, Davies A, Cauchi JA, Risbridger GP, Bertram JF. Fibroblast growth factor receptors and their ligands in the adult rat kidney. Kidney Int 60: 147-155, 2001.
22. Carpenter TO, Insogna KL, Zhang JH, Ellis B, Nieman S, Simpson C, Olear E, Gundberg CM. Circulating levels of soluble Klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment and relationship to parathyroid status. J Clin Endocrinol Metab 95: 352-357, 2010.
23. Carrillo-Lopez N, Roman-Garcia P, Rodriguez-Rebollar A, Fernandez-Martin JL, Naves-Diaz M, Cannata-Andia JB. Indirect regulation of PTH by estrogens may require FGF23. J Am Soc Nephrol 20: 2009-2017, 2009.
24. Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro OM, Huang CL. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci USA 105: 9805-9810, 2008.
25. Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310: 490-493, 2005.
26. Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 104: 19796-19801, 2007.
27. Craver L, Marco MP, Martinez I, Rue M, Borras M, Martin ML, Sarro F, Valdivielso JM, Fernandez E. Mineral metabolism parameters throughout chronic kidney disease stages 1-5-achievement of K/DOQI target ranges. Nephrol Dial Transplant 22: 1171-1176, 2007.
28. Cunningham J, Gomes H, Seino Y, Chase LR. Abnormal 24-hydroxylation of 25-hydroxyvitamin D in the X-linked hypophosphatemic mouse. Endocrinology 112: 633-638, 1983.
29. David V, Martin A, Hedge AM, Drezner MK, Rowe PS. ASARM peptides: PHEXdependent and -independent regulation of serum phosphate. Am J Physiol Renal Physiol 300: F783-F791, 2011.
30. David V, Quarles LD. ASARM mineralization hypothesis: a bridge too far? J Bone Miner Res 25: 692-694, 2010.
31. De Groot T, Lee K, Langeslag M, Xi Q, Jalink K, Bindels RJ, Hoenderop JG. Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation. J Am Soc Nephrol 20: 1693-1704, 2009.
32. DeLuca S, Sitara D, Kang K, Marsell R, Jonsson K, Taguchi T, Erben RG, Razzaque MS, Lanske B. Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23. J Pathol 216: 345-355, 2008.
33. Dunham-Ems SM, Lee YW, Stachowiak EK, Pudavar H, Claus P, Prasad PN, Stachowiak MK. Fibroblast growth factor receptor-1 (FGFR1) nuclear dynamics reveal a novel mechanism in transcription control. Mol Biol Cell 20: 2401-2412, 2009.
34. Dupont J, Holzenberger M. IGF type 1 receptor: a cell cycle progression factor that regulates aging. Cell Cycle 2: 270-272, 2003.
35. Erben RG, Kohn B, Weiser H, Sinowatz F, Rambeck WA. Role of vitamin D metabolites in the prevention of the osteopenia induced by ovariectomy in the axial and appendicular skeleton of the rat. Z Ernahrungswiss 29: 229-248, 1990.
36. Fang MA, Glackin CA, Sadhu A, McDougall S. Transcriptional regulation of alpha 2(I) collagen gene expression by fibroblast growth factor-2 in MC3T3-E1 osteoblast-like cells. J Cell Biochem 80: 550-559, 2001.
37. Faroqui S, Levi M, Soleimani M, Amlal H. Estrogen downregulates the proximal tubule type IIa sodium phosphate cotransporter causing phosphate wasting and hypophosphatemia. Kidney Int 73: 1141-1150, 2008.
38. Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 20: 955-960, 2009.
39. Fazekas G, Fazekas F, Schmidt R, Kapeller P, Offenbacher H, Krejs GJ. Brain MRI findings and cognitive impairment in patients undergoing chronic hemodialysis treatment. J Neurol Sci 134: 83-88, 1995.
40. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38: 1310-1315, 2006.
41. Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90: 1519-1524, 2005.
42. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, Ritz E, Kronenberg F, Kuen E, Konig P, Kraatz G, Mann JF, Muller GA, Kohler H, Riegler P. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 18: 2600-2608, 2007.
43. Fujiwara I, Aravindan R, Horst RL, Drezner MK. Abnormal regulation of renal 25- hydroxyvitamin D-1alpha-hydroxylase activity in X-linked hypophosphatemia: a translational or post-translational defect. J Bone Miner Res 18: 434-442, 2003.
44. Fukumoto S. Actions and mode of actions of FGF19 subfamily members. Endocr J 55: 23-31, 2008.
45. Fukumoto S, Yamashita T. Fibroblast growth factor-23 is the phosphaturic factor in tumor-induced osteomalacia and may be phosphatonin. Curr Opin Nephrol Hypertens 11: 385-389, 2002.
46. Galitzer H, Ben-Dov IZ, Silver J, Naveh-Many T. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 77: 211-218, 2010.
47. Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 297: F282-F291, 2009.
48. Gericke A, Qin C, Sun Y, Redfern R, Redfern D, Fujimoto Y, Taleb H, Butler WT, Boskey AL. Different forms of DMP1 play distinct roles in mineralization. J Dent Res 89: 355-359, 2010.
49. Gilsanz V, Kremer A, Mo AO, Wren TA, Kremer R. Vitamin D status and its relation to muscle mass and muscle fat in young women. J Clin Endocrinol Metab 95: 1595-1601, 2010.
50. Goebel S, Lienau J, Rammoser U, Seefried L, Wintgens KF, Seufert J, Duda G, Jakob F, Ebert R. FGF23 is a putative marker for bone healing and regeneration. J Orthop Res 27: 1141-1146, 2009.
51. Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert TA, Zhang F, Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuro-o M, Lanske B, Razzaque MS, Mohammadi M. Molec-ular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 27: 3417-3428, 2007.
52. Goldfarb M, Schoorlemmer J, Williams A, Diwakar S, Wang Q, Huang X, Giza J, Tchetchik D, Kelley K, Vega A, Matthews G, Rossi P, Ornitz DM, D'Angelo E. Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. Neuron 55: 449-463, 2007.
53. Guo R, Liu S, Spurney RF, Quarles LD. Analysis of recombinant Phex: an endopeptidase in search of a substrate. Am J Physiol Endocrinol Metab 281: E837-E847, 2001.
54. Gupta A, Winer K, Econs MJ, Marx SJ, Collins MT. FGF-23 is elevated by chronic hyperphosphatemia. J Clin Endocrinol Metab 89: 4489-4492, 2004.
55. Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N, Haystead TA, Donoghue M, Breitbart RE, Acton SL, Rockman HA, Coffman TM. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 116: 2218-2225, 2006.
56. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16: 2205-2215, 2005.
57. Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann U, Coglianese E, Christenson R, Wang TJ, deFilippi C, Wolf M. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119: 2545-2552, 2009.
58. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359: 584-592, 2008.
59. Haruna Y, Kashihara N, Satoh M, Tomita N, Namikoshi T, Sasaki T, Fujimori T, Xie P, Kanwar YS. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci USA 104: 2331-2336, 2007.
60. Hasegawa H, Nagano N, Urakawa I, Yamazaki Y, Iijima K, Fujita T, Yamashita T, Fukumoto S, Shimada T. 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. Kidney Int 78: 975-980, 2010.
61. He G, George A. Dentin matrix protein 1 immobilized on type I collagen fibrils facilitates apatite deposition in vitro. J Biol Chem 279: 11649-11656, 2004.
62. Hesse M, Frohlich LF, Zeitz U, Lanske B, Erben RG. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol 26: 75-84, 2007.
63. Hobo A, Yuzawa Y, Kosugi T, Kato N, Asai N, Sato W, Maruyama S, Ito Y, Kobori H, Ikematsu S, Nishiyama A, Matsuo S, Kadomatsu K. The growth factor midkine regulates the renin-angiotensin system in mice. J Clin Invest 119: 1616-1625, 2009.
64. Hodgson SF, Clarke BL, Tebben PJ, Mullan BP, Cooney WP 3rd, Shives TC. Oncogenic osteomalacia: localization of underlying peripheral mesenchymal tumors with use of Tc 99m sestamibi scintigraphy. Endocr Pract 12: 35-42, 2006.
65. Hoffman WH, Jain A, Chen H, Fedarko NS. Matrix extracellular phosphoglycoprotein (MEPE) correlates with serum phosphorus prior to and during octreotide treatment and following excisional surgery in hypophosphatemic linear sebaceous nevus syndrome. Am J Med Genet A 146: 2164-2168, 2008.
66. Hoffman WH, Jueppner HW, Deyoung BR, O'Dorisio MS, Given KS. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 134: 233-236, 2005.
67. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421: 182-187, 2003.
68. Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci 337: 116-122, 2009.
69. Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque MS, Rosenblatt KP, Baum MG, Kuro-o M, Moe OW. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24: 3438-3450, 2010.
70. Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, Moe OW. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22: 124-136, 2011.
71. Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117: 2684-2691, 2007.
72. Imai M, Ishikawa K, Matsukawa N, Kida I, Ohta J, Ikushima M, Chihara Y, Rui X, Rakugi H, Ogihara T. Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression. Endocrine 25: 229-234, 2004.
73. Imanishi Y, Inaba M, Nakatsuka K, Nagasue K, Okuno S, Yoshihara A, Miura M, Miyauchi A, Kobayashi K, Miki T, Shoji T, Ishimura E, Nishizawa Y. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 65: 1943-1946, 2004.
74. Imel EA, DiMeglio LA, Hui SL, Carpenter TO, Econs MJ. Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab 95: 1846-1850, 2010.
75. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y. alpha-Klotho as a regulator of calcium homeostasis. Science 316: 1615-1618, 2007.
76. Inoue Y, Segawa H, Kaneko I, Yamanaka S, Kusano K, Kawakami E, Furutani J, Ito M, Kuwahata M, Saito H, Fukushima N, Kato S, Kanayama HO, Miyamoto K. Role of the vitamin D receptor in FGF23 action on phosphate metabolism. Biochem J 390: 325-331, 2005.
77. Isakova T, Gutierrez OM, Smith K, Epstein M, Keating LK, Juppner H, Wolf M. Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease. Nephrol Dial Transplant 26: 584-591, 2011.
78. Ishii M, Yamaguchi Y, Yamamoto H, Hanaoka Y, Ouchi Y. Airspace enlargement with airway cell apoptosis in klotho mice: a model of aging lung. J Gerontol A Biol Sci Med Sci 63: 1289-1298, 2008.
79. Itoh N. Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease. Cell Tissue Res 342: 1-11, 2010.
80. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 20: 563-569, 2004.
81. Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn 237: 18-27, 2008.
82. Jean G, Bresson E, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B, Chazot C. Peripheral vascular calcification in long-haemodialysis patients: associated factors and survival consequences. Nephrol Dial Transplant 24: 948-955, 2009.
83. Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev 78: 1193-1231, 1998.
84. Kamemori M, Ohyama Y, Kurabayashi M, Takahashi K, Nagai R, Furuya N. Expression of Klotho protein in the inner ear. Hear Res 171: 103-110, 2002.
85. Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 281: 18370-18377, 2006.
86. Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M. Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104: 229-237, 1999.
87. Kawata T, Imanishi Y, Kobayashi K, Miki T, Arnold A, Inaba M, Nishizawa Y. Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. J Am Soc Nephrol 18: 2683-2688, 2007.
88. Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T, Sugimura K, Kishimoto T, Kinoshita S, Kuroki T, Nabeshima Y. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280: 1015-1020, 2001.
89. Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK. 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289: G1036-G1042, 2005.
90. Komaba H, Fukagawa M. FGF23-parathyroid interaction: implications in chronic kidney disease. Kidney Int 77: 292-298, 2010.
91. Komaba H, Goto S, Fujii H, Hamada Y, Kobayashi A, Shibuya K, Tominaga Y, Otsuki N, Nibu K, Nakagawa K, Tsugawa N, Okano T, Kitazawa R, Fukagawa M, Kita T. Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney Int 77: 232-238, 2010.
92. Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, Westin G, Larsson TE. Fibroblast growth factor-23 regulates parathyroid hormone and 1alphahydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195: 125-131, 2007.
93. Kremer R, Campbell PP, Reinhardt T, Gilsanz V. Vitamin D status and its relationship to body fat, final height, and peak bone mass in young women. J Clin Endocrinol Metab 94: 67-73, 2009.
94. Kuro-o M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/ calcium metabolism. Curr Opin Nephrol Hypertens 15: 437-441, 2006.
95. +-proton exchanger. Circ Res 76: 148-153, 1995.
96. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45-51, 1997.
97. Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 282: 26687-26695, 2007.
98. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281: 6120-6123, 2006.
99. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M. Suppression of aging in mice by the hormone Klotho. Science 309: 1829-1833, 2005.
100. Kwiatkowski BA, Kirillova I, Richard RE, Israeli D, Yablonka-Reuveni Z. FGFR4 and its novel splice form in myogenic cells: interplay of glycosylation and tyrosine phosphorylation. J Cell Physiol 215: 803-817, 2008.
101. Lanske B, Razzaque MS. Mineral metabolism and aging: the fibroblast growth factor 23 enigma. Curr Opin Nephrol Hypertens 16: 311-318, 2007.
102. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Juppner H, Jonsson KB. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145: 3087-3094, 2004.
103. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. 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. Kidney Int 64: 2272-2279, 2003.
104. Larsson TE. The role of FGF-23 in CKD-MBD and cardiovascular disease: friend or foe? Nephrol Dial Transplant 25: 1376-1381, 2010.
105. Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 299: F882-F889, 2010.
106. Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 86: 273-278, 2010.
107. Li H, Martin A, David V, Quarles LD. Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. Am J Physiol Endocrinol Metab 300: E508-E517, 2011.
108. Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 29: 91-99, 2004.
109. Liang H, Pun S, Wronski TJ. Bone anabolic effects of basic fibroblast growth factor in ovariectomized rats. Endocrinology 140: 5780-5788, 1999.
110. Liel Y, Shany S, Smirnoff P, Schwartz B. Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinology 140: 280-285, 1999.
111. Lin BC, Wang M, Blackmore C, Desnoyers LR. Liver-specific activities of FGF19 require Klotho beta. J Biol Chem 282: 27277-27284, 2007.
112. Liu S, Brown TA, Zhou J, Xiao ZS, Awad H, Guilak F, Quarles LD. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. J Am Soc Nephrol 16: 1645-1653, 2005.
113. Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 278: 37419-37426, 2003.
114. Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 18: 1637-1647, 2007.
115. Liu S, Rowe PS, Vierthaler L, Zhou J, Quarles LD. Phosphorylated acidic serineaspartate- rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity. J Endocrinol 192: 261-267, 2007.
116. Liu S, Tang W, Fang J, Ren J, Li H, Xiao Z, Quarles LD. Novel regulators of Fgf23 expression and mineralization in Hyp bone. Mol Endocrinol 23: 1505-1518, 2009.
117. Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17: 1305-1315, 2006.
118. Liu S, Tang W, Zhou J, Vierthaler L, Quarles LD. Distinct roles for intrinsic osteocyte abnormalities and systemic factors in regulation of FGF23 and bone mineralization in Hyp mice. Am J Physiol Endocrinol Metab 293: E1636-E1644, 2007.
119. Liu S, Vierthaler L, Tang W, Zhou J, Quarles LD. FGFR3 and FGFR4 do not mediate renal effects of FGF23. J Am Soc Nephrol 19: 2342-2350, 2008.
120. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291: E38-E49, 2006.
121. Liu S, Zhou J, Tang W, Menard R, Feng JQ, Quarles LD. Pathogenic role of Fgf23 in Dmp1-null mice. Am J Physiol Endocrinol Metab 295: E254-E261, 2008.
122. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ, Glorieux F, Vikkula M, Juppner H, Strom TM. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38: 1248-1250, 2006.
123. Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal- recessive hypophosphatemic rickets. Am J Hum Genet 86: 267-272, 2010.
124. Lu P, Boros S, Chang Q, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho exclusively activates the epithelial Ca2_ channels TRPV5 and TRPV6. Nephrol Dial Transplant 23: 3397-3402, 2008.
125. Lu Y, Qin C, Xie Y, Bonewald LF, Feng JQ. Studies of the DMP1 57-kDa Functional Domain both in vivo and in vitro. Cells Tissues Organs 189: 175-185, 2009.
126. Lu Y, Yuan B, Qin C, Cao Z, Xie Y, Dallas SL, McKee MD, Drezner MK, Bonewald LF, Feng JQ. The biological function of DMP1 in osteocyte maturation is mediated by its 57 kDa C-terminal fragment. J Bone Miner Res 26: 331-340, 2011.
127. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21: 115-137, 2000.
128. Marsell R, Krajisnik T, Goransson H, Ohlsson C, Ljunggren O, Larsson TE, Jonsson KB. Gene expression analysis of kidneys from transgenic mice expressing fibroblast growth factor-23. Nephrol Dial Transplant 23: 827-833, 2008.
129. Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM, Rowe PS. Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology 149: 1757-1772, 2008.
130. Martin A, Liu S, David V, Li H, Karydis A, Feng JQ, Quarles LD. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25: 2551-2562, 2011.
131. Martuseviciene G, Hofman-Bang J, Clausen T, Olgaard K, Lewin E. The secretory response of parathyroid hormone to acute hypocalcemia in vivo is independent of parathyroid glandular sodium/potassium-ATPase activity. Kidney Int 79: 742-748, 2011.
132. Masi L, Beltrami G, Gozzini A, Ottanelli S, Amedei A, Falchetti A, Casentini C, Fossi C, Brandi M. A case of tumoral calcinosis-hyperphosphatemia due to a novel mutation in GALNT3 gene. J Bone Miner Res 24 Suppl 1, 2009.
133. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242: 626-630, 1998.
134. Matsunuma A, Horiuchi N. Leptin attenuates gene expression for renal 25-hydroxyvitamin D3-1alpha-hydroxylase in mice via the long form of the leptin receptor. Arch Biochem Biophys 463: 118-127, 2007.
135. Matsunuma A, Kawane T, Maeda T, Hamada S, Horiuchi N. Leptin corrects increased gene expression of renal 25-hydroxyvitamin D3-1 alpha-hydroxylase and -24-hydroxylase in leptin-deficient, ob/ob mice. Endocrinology 145: 1367-1375, 2004.
136. Meyer MH, Dulde E, Meyer RA Jr. The genomic response of the mouse kidney to low-phosphate diet is altered in X-linked hypophosphatemia. Physiol Genomics 18: 4-11, 2004.
137. Mirza MA, Alsio J, Hammarstedt A, Erben RG, Michaelsson K, Tivesten A, Marsell R, Orwoll E, Karlsson MK, Ljunggren O, Mellstrom D, Lind L, Ohlsson C, Larsson TE. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arterioscler Thromb Vasc Biol 31: 219-227, 2011.
138. Mirza MA, Hansen T, Johansson L, Ahlstrom H, Larsson A, Lind L, Larsson TE. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant 24: 3125-3131, 2009.
139. Mirza MA, Larsson A, Lind L, Larsson TE. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 205: 385-390, 2009.
140. Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207: 546-551, 2009.
141. Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S, Suzuki T, Amaki T, Mori I, Nakamura Y, Sato M, Nangaku M, Hirata Y, Nagai R. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 39: 838-843, 2002.
142. Miyamoto K, Ito M, Kuwahata M, Kato S, Segawa H. Inhibition of intestinal sodiumdependent inorganic phosphate transport by fibroblast growth factor 23. Ther Apher Dial 9: 331-335, 2005.
143. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69: 1945-1953, 2006.
144. Mori S, Wu CY, Yamaji S, Saegusa J, Shi B, Ma Z, Kuwabara Y, Lam KS, Isseroff RR, Takada YK, Takada Y. Direct binding of integrin alphavbeta3 to FGF1 plays a role in FGF1 signaling.J Biol Chem 283: 18066-18075, 2008.
145. Nabeshima Y. Toward a better understanding of Klotho. Sci Aging Knowledge Environ 2006: pe11, 2006.
146. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, Nabeshima T. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 17: 50-52, 2003.
147. Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M. Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int 69: 531-537, 2006.
148. Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, Mohammadi M, Lanske B, Razzaque MS. In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23)-mediated regulation of systemic phosphate homeostasis. FASEB J 23: 433-441, 2009.
149. 2+ store. J Biol Chem 278: 17500-17508, 2003.
150. Nauman EA, Sakata T, Keaveny TM, Halloran BP, Bikle DD. bFGF administration lowers the phosphate threshold for mineralization in bone marrow stromal cells. Calcif Tissue Int 73: 147-152, 2003.
151. Naveh-Many T, Almogi G, Livni N, Silver J. Estrogen receptors and biologic response in rat parathyroid tissue and C cells. J Clin Invest 90: 2434-2438, 1992.
152. Nishida Y, Taketani Y, Yamanaka-Okumura H, Imamura F, Taniguchi A, Sato T, Shuto E, Nashiki K, Arai H, Yamamoto H, Takeda E. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int 70: 2141-2147, 2006.
153. Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M. BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 104: 7432-7437, 2007.
154. Ogbureke KU, Fisher LW. Expression of SIBLINGs and their partner MMPs in salivary glands. J Dent Res 83: 664-670, 2004.
155. Okada S, Yoshida T, Hong Z, Ishii G, Hatano M, Kuro OM, Nabeshima Y, Tokuhisa T. Impairment of B lymphopoiesis in precocious aging (klotho) mice. Int Immunol 12: 861-871, 2000.
156. Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, Carvalho AB, Jorgetti V, Canziani ME, Moyses RM. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 5: 286-291, 2010.
157. Parker BD, Schurgers LJ, Brandenburg VM, Christenson RH, Vermeer C, Ketteler M, Shlipak MG, Whooley MA, Ix JH. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med 152: 640-648, 2010.
158. Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25- dihydroxyvitamin D metabolism in mice. Endocrinology 146: 5358-5364, 2005.
159. Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol 293: F1577-F1583, 2007.
160. Prentice A, Ceesay M, Nigdikar S, Allen SJ, Pettifor JM. FGF23 is elevated in Gambian children with rickets. Bone 42: 788-797, 2008.
161. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118: 3820-3828, 2008.
162. Quarles LD. Evidence for a bone-kidney axis regulating phosphate homeostasis. J Clin Invest 112: 642-646, 2003.
163. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 115: 3318-3325, 2005.
164. Rowe PS, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR. MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 34: 303-319, 2004.
165. +-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem 278: 2206-2211, 2003.
166. 3 and phosphorus in vivo. J Biol Chem 280: 2543-2549, 2005.
167. Saji F, Shigematsu T, Sakaguchi T, Ohya M, Orita H, Maeda Y, Ooura M, Mima T, Negi S. Fibroblast growth factor 23 production in bone is directly regulated by 1α,25- dihydroxyvitamin D, but not PTH. Am J Physiol Renal Physiol 299: F1212-F1217, 2010.
168. Samadfam R, Richard C, Nguyen-Yamamoto L, Bolivar I, Goltzman D. Bone formation regulates circulating concentrations of fibroblast growth factor 23. Endocrinology 150: 4835-4845, 2009.
169. Sato A, Hirai T, Imura A, Kita N, Iwano A, Muro S, Nabeshima Y, Suki B, Mishima M. Morphological mechanism of the development of pulmonary emphysema in klotho mice. Proc Natl Acad Sci USA 104: 2361-2365, 2007.
170. Sato T, Tominaga Y, Ueki T, Goto N, Matsuoka S, Katayama A, Haba T, Uchida K, Nakanishi S, Kazama JJ, Gejyo F, Yamashita T, Fukagawa M. Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism. Am J Kidney Dis 44: 481-487, 2004.
171. Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem 46: 167-169, 2009.
172. Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab 94: 2332-2337, 2009.
173. Segawa H, Yamanaka S, Ohno Y, Onitsuka A, Shiozawa K, Aranami F, Furutani J, Tomoe Y, Ito M, Kuwahata M, Imura A, Nabeshima Y, Miyamoto K. Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice. Am J Physiol Renal Physiol 292: F769-R779, 2007.
174. Sehgal AR, Grey SF, DeOreo PB, Whitehouse PJ. Prevalence, recognition, and implications of mental impairment among hemodialysis patients. Am J Kidney Dis 30: 41-49, 1997.
175. Shalhoub V, Ward SC, Sun B, Stevens J, Renshaw L, Hawkins N, Richards WG. Fibroblast Growth Factor 23 (FGF23) and Alpha-Klotho Stimulate Osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization. Calcif Tissue Int 89: 140-150, 2011.
176. Shigematsu T, Kazama JJ, Yamashita T, Fukumoto S, Hosoya T, Gejyo F, Fukagawa M. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 44: 250-256, 2004.
177. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19: 429-435, 2004.
178. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113: 561-568, 2004.
179. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 98: 6500-6505, 2001.
180. Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143: 3179-3182, 2002.
181. Shimada T, Takeshita Y, Murohara T, Sasaki K, Egami K, Shintani S, Katsuda Y, Ikeda H, Nabeshima Y, Imaizumi T. Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse. Circulation 110: 1148-1155, 2004.
182. Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 314: 409-414, 2004.
183. Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, Ono K, Kakitani M, Tomizuka K, Fujita T, Fukumoto S, Yamashita T. Vitamin D receptorindependent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 289: F1088-F1095, 2005.
184. Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N, Fukumoto S, Sugimoto T, Fujita T. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone 45: 814-816, 2009.
185. Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, Nagai R, Kuro-o M, Nabeshima Y. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 424: 6-10, 1998.
186. Sitara D, Kim S, Razzaque MS, Bergwitz C, Taguchi T, Schuler C, Erben RG, Lanske B. Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genet 4: e1000154, 2008.
187. Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Juppner H, Lanske B. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23: 421-432, 2004.
188. Sitara D, Razzaque MS, St-Arnaud R, Huang W, Taguchi T, Erben RG, Lanske B. Genetic ablation of vitamin d activation pathway reverses biochemical and skeletal anomalies in fgf-23-null animals. Am J Pathol 169: 2161-2170, 2006.
189. Specktor P, Cooper JG, Indelman M, Sprecher E. Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred. J Hum Genet 51: 487-490, 2006.
190. Stewart I, Roddie C, Gill A, Clarkson A, Mirams M, Coyle L, Ward C, Clifton-Bligh P, Robinson BG, Mason RS, Clifton-Bligh RJ. Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone 39: 369-376, 2006.
191. Stubbs J, Liu S, Tang W, Quarles LD. Role of hyperphosphatemia and 1,25(OH)2D3 in vascular calcifications and mortality in FGF23 null mice. J Am Soc Nephrol 17: 689A, 2006.
192. Stubbs JR, Idiculla A, Slusser J, Menard R, Quarles LD. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol 21: 353-361, 2010.
193. Stubbs JR, Liu S, Tang W, Zhou J, Wang Y, Yao X, Quarles LD. Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 18: 2116-2124, 2007.
194. Stubbs JR, Quarles LD. Fibroblast growth factor 23: uremic toxin or innocent bystander in chronic kidney disease? Nephrol News Issues 23: 33-37, 2009.
195. Sun Y, Prasad M, Gao T, Wang X, Zhu Q, D'Souza R, Feng JQ, Qin C. Failure to process dentin matrix protein 1 (DMP1) into fragments leads to its loss of function in osteogenesis. J Biol Chem 285: 31713-31722, 2010.
196. Takeshita K, Fujimori T, Kurotaki Y, Honjo H, Tsujikawa H, Yasui K, Lee JK, Kamiya K, Kitaichi K, Yamamoto K, Ito M, Kondo T, Iino S, Inden Y, Hirai M, Murohara T, Kodama I, Nabeshima Y. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 109: 1776-1782, 2004.
197. Takumida M, Ishibashi T, Hamamoto T, Hirakawa K, Anniko M. Age-dependent changes in the expression of klotho protein, TRPV5 and TRPV6 in mouse inner ear. Acta Otolaryngol 1-11, 2009.
198. Ten Bolscher M, Netelenbos JC, Barto R, Van Buuren LM, Van der vijgh WJ. Estrogen regulation of intestinal calcium absorption in the intact and ovariectomized adult rat. J Bone Miner Res 14: 1197-1202, 1999.
199. Tenenhouse HS. Metabolism of 25-hydroxyvitamin D3 in renal slices from the Xlinked hypophosphatemic (Hyp) mouse: abnormal response to fall in serum calcium. Cell Calcium 5: 43-55, 1984.
200. Teti A, Zallone A. Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone 44: 11-16, 2009.
201. Thisse B, Thisse C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol 287: 390-402, 2005.
202. Tohyama O, Imura A, Iwano A, Freund JN, Henrissat B, Fujimori T, Nabeshima Y. Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 279: 9777-9784, 2004.
203. Tomiyama K, Maeda R, Urakawa I, Yamazaki Y, Tanaka T, Ito S, Nabeshima Y, Tomita T, Odori S, Hosoda K, Nakao K, Imura A. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc Natl Acad Sci USA 107: 1666-1671, 2010.
204. Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36: 579-581, 2004.
205. Tsuji K, Maeda T, Kawane T, Matsunuma A, Horiuchi N. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D(3) synthesis in leptin-deficient ob/ob mice. J Bone Miner Res 25: 1711-1723, 2010.
206. Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 17: 2393-2403, 2003.
207. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770-774, 2006.
208. Wang H, Yamamoto R, Tanne K, Aubin JE, Maeda N, Yoahiko Y. Adenovirus-mediated overexpression of FGF23 suppresses osteoblast development and matrix mineralization in fetal rat calvaria cell cultures. J Bone Miner Res 20: S128, 2005.
209. Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K, Tanne K, Aubin JE, Maeda N. Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J Bone Miner Res 23: 939-948, 2008.
210. Wang Y, Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension 54: 810-817, 2009.
211. Weber TJ, Liu S, Indridason OS, Quarles LD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 18: 1227-1234, 2003.
212. Weinstein M, Xu X, Ohyama K, Deng CX. FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. Development 125: 3615-3623, 1998.
213. Westerberg PA, Linde T, Wikstrom B, Ljunggren O, Stridsberg M, Larsson TE. Regulation of fibroblast growth factor-23 in chronic kidney disease. Nephrol Dial Transplant 22: 3202-3207, 2007.
214. Wetmore JB, Liu S, Krebill R, Menard R, Quarles LD. Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD. Clin J Am Soc Nephrol 2009.
215. Wetmore JB, Quarles LD. Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift? Nat Clin Pract Nephrol 5: 24-33, 2009.
216. White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, Fitzpatrick D, Yu K, Ornitz DM, Econs MJ. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76: 361-367, 2005.
217. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. Autosomal- dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 60: 2079-2086, 2001.
218. Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, Kuro-o M, Karlan B, Kaufman B, Koeffler HP, Rubinek T. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 27: 7094-7105, 2008.
219. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol 21: 1427-1435, 2010.
220. Wronski TJ, Halloran BP, Bikle DD, Globus RK, Morey-Holton ER. Chronic administration of 1,25-dihydroxyvitamin D3: increased bone but impaired mineralization. Endocrinology 119: 2580-2585, 1986.
221. Xiao L, Liu P, Li X, Doetschman T, Coffin JD, Drissi H, Hurley MM. Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice. J Biol Chem 284: 3170-3182, 2009.
222. Xiao L, Naganawa T, Lorenzo J, Carpenter TO, Coffin JD, Hurley MM. Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO. J Biol Chem 285: 2834-2846, 2010.
223. Xiao M, Xu L, Laezza F, Yamada K, Feng S, Ornitz DM. Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14. Mol Cell Neurosci 34: 366-377, 2007.
224. Yamashita T, Konishi M, Miyake A, Inui K, Itoh N. Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway. J Biol Chem 277: 28265-28270, 2002.
225. Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 277: 494-498, 2000.
226. Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87: 4957-4960, 2002.
227. Yu J, Deng M, Zhao J, Huang L. Decreased expression of klotho gene in uremic atherosclerosis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun 391: 261-266, 2010.
228. Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, Mohammadi M, White KE. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 146: 4647-4656, 2005.
229. Yu X, Sabbagh Y, Davis SI, Demay MB, White KE. Genetic dissection of phosphateand vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone 36: 971-977, 2005.
230. Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, Xie Y, Drezner MK. Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest 118: 722-734, 2008.
231. Yuan B, Xing Y, Horst RL, Drezner MK. Evidence for abnormal translational regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in the hyp-mouse. Endocrinology 145: 3804-3812, 2004.
232. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281: 15694-15700, 2006.