Circulating FGF-23 Is Regulated by 1α,25-Dihydroxyvitamin D3 and Phosphorus in Vivo

Fibroblast growth factor-23 (FGF-23), a novel phosphate-regulating factor, was elevated in hypophosphatemic patients with X-linked hypophosphatemic rickets/osteomalacia and also in patients with chronic kidney disease. These observations suggested the pathophysiological importance of FGF-23 on phosphate homeostasis. However, regulation of FGF-23 production is still unclear. We investigated effects of both dietary phosphorus and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) on circulating FGF-23 in vivo Administration of. 1α,25(OH)2D3 dose-dependently increased serum FGF-23 in thyroparathyroidectomized rats without correlating with serum inorganic phosphorus or serum parathyroid hormone. On the other hand, vitamin D receptor null mice had very low serum FGF-23 and did not respond to the 1α,25(OH)2D3 administration. These observations suggested 1α,25(OH)2D3 directly or indirectly regulates circulating FGF-23. Serum FGF-23 had a strong correlation with serum inorganic phosphorus controlled by dietary phosphorus in 5/6 nephrectomized rats. High phosphate diet elicited a 5-fold increase in serum FGF-23 compared with sham-operated rats, whereas serum FGF-23 did not correlate with serum calcium or serum creatinine in 5/6 nephrectomized rats. Administration of 1α,25-dihydroxyvitamin D3 also elicited a severalfold increase in serum FGF-23 in the uremic rats. Taken together, this shows that both serum phosphorus and 1α,25(OH)2D3 regulate circulating FGF-23 independent of each other. Therefore, we proposed there was a feedback loop existing among serum phosphorus, 1α,25(OH)2D3, and FGF-23, in which the novel phosphate-regulating bone-kidney axis integrated with the parathyroid hormone-vitamin D3 axis in regulating phosphate homeostasis. Fibroblast growth factor-23 (FGF-23), a novel phosphate-regulating factor, was elevated in hypophosphatemic patients with X-linked hypophosphatemic rickets/osteomalacia and also in patients with chronic kidney disease. These observations suggested the pathophysiological importance of FGF-23 on phosphate homeostasis. However, regulation of FGF-23 production is still unclear. We investigated effects of both dietary phosphorus and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) on circulating FGF-23 in vivo Administration of. 1α,25(OH)2D3 dose-dependently increased serum FGF-23 in thyroparathyroidectomized rats without correlating with serum inorganic phosphorus or serum parathyroid hormone. On the other hand, vitamin D receptor null mice had very low serum FGF-23 and did not respond to the 1α,25(OH)2D3 administration. These observations suggested 1α,25(OH)2D3 directly or indirectly regulates circulating FGF-23. Serum FGF-23 had a strong correlation with serum inorganic phosphorus controlled by dietary phosphorus in 5/6 nephrectomized rats. High phosphate diet elicited a 5-fold increase in serum FGF-23 compared with sham-operated rats, whereas serum FGF-23 did not correlate with serum calcium or serum creatinine in 5/6 nephrectomized rats. Administration of 1α,25-dihydroxyvitamin D3 also elicited a severalfold increase in serum FGF-23 in the uremic rats. Taken together, this shows that both serum phosphorus and 1α,25(OH)2D3 regulate circulating FGF-23 independent of each other. Therefore, we proposed there was a feedback loop existing among serum phosphorus, 1α,25(OH)2D3, and FGF-23, in which the novel phosphate-regulating bone-kidney axis integrated with the parathyroid hormone-vitamin D3 axis in regulating phosphate homeostasis. The parathyroid hormone-vitamin D3 endocrine system, as well as dietary phosphorus, plays an important role in regulating renal and gastrointestinal absorption of phosphate. Recently, emerging evidence suggests that other systemic and/or paracrine/autocrine factors are present in bones for maintaining phosphate homeostasis, such as fibroblast growth factor-23 (FGF-23), 1The abbreviations used are: FGF-23, fibroblast growth factor-23; Pi, phosphate; IP, inorganic phosphorus; TPTX, thyroparathyroidectomy; XLH, X-linked hypophosphatemia; PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; 1α,25(OH)2D3, 1α,25-dihydroxyvitamin D3; 1α-OHase, 25-hydroxyvitamin D3 1α-hydroxylase; PTH, parathyroid hormone; ELISA, enzymelinked immunosorbent assay; VDRKO, vitamin D receptor null(–/–). frizzled-related protein-4 (FRP-4), and matrix extracellular phosphoglycoprotein (MEPE) (1The ADHR, ConsortiumNat. 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Among these factors, FGF-23 strongly suppressed 1α,25(OH)2D3 production and elicited hypophosphatemia. Administration of the recombinant FGF-23 protein reduced serum phosphorus without affecting serum calcium, as well as increasing renal phosphorus excretion in mice (12Shimada T. Muto T. Urakawa I. Yoneya T. Yamazaki Y. Okawa K. Takeuchi Y. Fujita T. Fukumoto S. Yamashita T. Endocrinology. 2002; 143: 3179-3182Crossref PubMed Scopus (387) Google Scholar). Mice bearing FGF-23-expressing Chinese hamster ovary cells showed suppressed 25-hydroxyvitamin D3 1α-hydroxylase mRNA expression in the kidney (3Shimada T. Mizutani S. Muto T. Yoneya T. Hino R. Takeda S. Takeuchi Y. Fujita T. Fukumoto S. Yamashita T. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6500-6505Crossref PubMed Scopus (1231) Google Scholar). FGF-23 mRNA is expressed in a variety of tissues such as thymus, brain, bone, thyroid/parathyroid gland, and heart (2Yamashita T. Yoshioka M. Ito N. Biochem. Biophys. Res. Commun. 2000; 277: 494-498Crossref PubMed Scopus (451) Google Scholar, 3Shimada T. Mizutani S. Muto T. Yoneya T. Hino R. Takeda S. Takeuchi Y. Fujita T. Fukumoto S. Yamashita T. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6500-6505Crossref PubMed Scopus (1231) Google Scholar, 13Liu S. Guo R. Simpson L.G. Xian Z-S. Burnham C.E. Quarles L.D. J. Biol. Chem. 2003; 278: 37419-37426Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). Recent studies (13Liu S. Guo R. Simpson L.G. Xian Z-S. Burnham C.E. Quarles L.D. J. Biol. Chem. 2003; 278: 37419-37426Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 14Riminucci M. Collins M.T. Fedaeko N.S. Cherman N. Corsi A. White K.E. Waguespack S. Gupta A. Hannon T. Econs M.J. Bianco P. Robey P.G. J. Clin. Invest. 2003; 112: 683-692Crossref PubMed Scopus (553) Google Scholar) indicated FGF-23 mRNA as well as FGF-23 protein was elevated in bones from patients with McCune-Albright syndrome and also in bones from HYP mouse, mouse homologue to X-linked hypophosphatemic (XLH) rickets. However, the level of serum FGF-23 in hypophosphatemic patients with XLH is still controversial (15Yamazaki Y. Okazaki R. Shibata M. Hasegawa Y. Satoh K. Tajima T. Takeuchi Y. Fujita T. Nakahara K. Yamashita T. Fukumoto S. J. Clin. Endocrinol. Metab. 2002; 87: 4957-4960Crossref PubMed Scopus (582) Google Scholar, 16Webber T.J. Liu S. Indridason O.S. Quarles L.D. J. Bone Miner. Res. 2003; 18: 1227-1234Crossref PubMed Scopus (310) Google Scholar, 17Jonsson K.B. Zahradnik R. Larsson T. White K.E. Sugimoto T. Imanishi Y. Yamamoto T. Hampson G. Koshiyama H. Ljuggren Ö. Oba K. Yang I.M. Miyauchi A. Econs M.J. Lavigne J. Jüppner H. N. Eng. J. Med. 2003; 348: 1656-1663Crossref PubMed Scopus (784) Google Scholar). Hyperphosphatemic patients with chronic kidney disease showed significant elevation in circulating FGF-23, which correlated with serum phosphorus and creatinine (16Webber T.J. Liu S. Indridason O.S. Quarles L.D. J. Bone Miner. Res. 2003; 18: 1227-1234Crossref PubMed Scopus (310) Google Scholar, 18Larsson T. Nisbeth U. Ljunggren Ö. Jüppner H. Jonsson K.B. Kidney Int. 2003; 64: 2272-2279Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 19Imanishi 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. Kidney Int. 2004; 65: 1943-1946Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 20Shigematsu T. Kazama J.J. Yamashita T. Fukumoto S. Hosoya T. Geyjo F. Fukagawa M. Am. J. Kidney Dis. 2004; 44: 250-256Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar), suggesting (a) serum phosphorus was a possible regulator of FGF-23 production or (b) circulating FGF-23 accumulated in chronic renal failure. The purpose of this study was to evaluate the effects of dietary phosphorus and 1α,25(OH)2D3 on FGF-23 production. Administration of FGF-23 protein or overexpression of Fgf23 gene in rodent suppressed 1α,25(OH)2D3 production by reducing 25-hydroxyvitamin D3 1α-hydroxylase in the proximal tubules (12Shimada T. Muto T. Urakawa I. Yoneya T. Yamazaki Y. Okawa K. Takeuchi Y. Fujita T. Fukumoto S. Yamashita T. Endocrinology. 2002; 143: 3179-3182Crossref PubMed Scopus (387) Google Scholar, 21Saito H. Kusano K. Kinosaki M. Ito H. Hirata M. Segawa H. Miyamoto K. Fukushima N. J. Biol. Chem. 2003; 278: 2206-2211Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 22Bai X.Y. Miao D. Goltzman D. Karaplis A.C. J. Biol. Chem. 2003; 278: 9843-9849Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 23Shimada T. Urakawa I. Yamazaki Y. Hasegawa H. Hino R. Yoneya T. Takeuchi Y. Fujita T. Fukumoto S. Yamashita T. Biochem. Biophys. Res. Comm. 2004; 314: 409-414Crossref PubMed Scopus (378) Google Scholar). On the contrary, Fgf23-null mice reported increased circulating 1α,25(OH)2D3 despite hyperphosphatemia, hypercalcemia, and low PTH levels (24Shimada T. Kakitani M. Yamazaki Y. Hasegawa H. Takeuchi Y. Fujita T. Fukumoto S. Tomizuka K. Yamashita T. J. Clin. Invest. 2004; 113: 561-568Crossref PubMed Scopus (1287) Google Scholar). Administration of 1α,25(OH)2D3 increased serum FGF-23 in normal mice (25Shimada T. Hasegawa H. Yamazaki Y. Muto T. Hino R. Takeuchi Y. Fujita T. Nakahara K. Fukumoto S. Yamashita T. J. Bone Miner. Res. 2004; 19: 429-435Crossref PubMed Scopus (1442) Google Scholar). These observations suggested mutual regulation between FGF-23 and 1α,25(OH)2D3; however, 1α,25(OH)2D3 administration also increases intestinal phosphate uptake and suppresses PTH. Thus, we used thyroparathyroidectomized rats as well as 5/6 nephrectomized rats fed a diet with various kinds of phosphorus content to examine the direct effect of 1α,25(OH)2D3 administration on serum FGF-23. Dietary phosphate deprivation or loading rapidly induces activation or repression of phosphate absorption in kidney and in intestine, mainly by inducing or suppressing type II sodium-dependent phosphate (Na/Pi) cotransporter expression (26Katai K. Miyamoto K. Kishida S. Segawa H. Nii T. Tanaka H. Tani Y. Arai H. Tatsumi S. Morita K. Taketani Y. Takeda E. Biochem. J. 1999; 343: 705-714Crossref PubMed Scopus (161) Google Scholar, 27Katai K. Segawa H. Haga H. Morita K. Arai H. Tatsumi S. Taketani Y. Miyamoto K. Hisano S. Fukui Y. Takeda E. J. Biochem. (Tokyo). 1997; 121: 50-55Crossref PubMed Scopus (49) Google Scholar). Therefore, the serum phosphorus level is not susceptible to the change in dietary phosphorus content in normal animals in vivo. We investigated the effects of dietary phosphorus on FGF-23 production in vivo using 5/6 nephrectomized uremic rats, in which the serum phosphorus level can be easily manipulated by dietary phosphorus due to reduced kidney function. We also examined the correlations between serum FGF-23 and (a) serum inorganic phosphorus, (b) serum calcium, (c) serum creatinine, and (d) serum PTH in 5/6 nephrectomized rats. Normal Rat—Eight-week-old male Sprague-Dawley rats (CREA Japan, Inc., Shizuoka, Japan) were given either vehicle, 10, 30, 100, or 300 ng of 1α,25(OH)2D3/kg of bodyweight intravenously, three times a week for 2 weeks. Blood samples were obtained from the vena cava under ether anesthesia on day 14. Serum calcium, serum inorganic phosphorus, and serum creatinine were measured by an automatic analyzer (Type 7170E, Hitachi Corp.). Serum FGF-23 was determined by the Human FGF-23 ELISA kit (Kinos Inc., Tokyo, Japan). Thyroparathyroidectomized (TPTX) Rats and PTH-infused TPTX Rats—Eight-week-old male Sprague-Dawley rats purchased from Charles River (Tokyo, Japan) were TPTX under ether anesthesia. After confirming hypocalcemia had been induced, rats were divided to two groups, the TPTX group and the TPTX + PTH group. Rats in the TPTX + PTH group were subcutaneously implanted with ALZET® osmotic pumps (model 2ML2, Durect Corp., Cupertino, CA) and administered human PTH-(1–34) at a constant rate of 2.4 μg/day for 14 days. Rats in the TPTX group were intravenously injected with vehicle, 50 ng/kg or 300 ng/kg 1α,25(OH)2D3, three times a week for 2 weeks; rats in the TPTX + PTH group were injected with either vehicle or 50 ng/kg 1α,25(OH)2D3 three times a week for 2 weeks. Blood samples were collected and various parameters analyzed as described above. Vitamin D Receptor Null(–/–) (VDRKO) Mice—VDRKO mice and their littermates kept on a high calcium and high phosphorus diet (28Yoshizawa T. Handa Y. Uematsu Y. Takeda S. Sekine K. Yoshihara Y. Kawakami T. Arioka K. Sato H. Uchiyama Y. Masushige S. Fukamizu A. Matsumoto T. Kato S. Nat. Genet. 1997; 6: 391-396Crossref Scopus (1001) Google Scholar) were administered vehicle or 300 ng/kg 1α,25(OH)2D3 three times a week for 2 weeks. Blood samples were collected and analyzed as described above. 5/6 Subtotally Nephrectomized Uremic Rat Models and Diets—Male Sprague-Dawley rats weighing 180–200 g were purchased from CREA Japan and maintained under specific pathogen-free conditions with a 12-h light/dark cycle. After acclimating for 1 week, the rats were 5/6 nephrectomized and then allowed to normal rodent CREA Japan and The phosphate and 1α,25(OH)2D3 serum creatinine the of Japan) were used in the present a high phosphorus, a phosphorus, and a low phosphorus, calcium (26Katai K. Miyamoto K. Kishida S. Segawa H. Nii T. Tanaka H. Tani Y. Arai H. Tatsumi S. Morita K. Taketani Y. Takeda E. Biochem. J. 1999; 343: 705-714Crossref PubMed Scopus (161) Google Scholar, 27Katai K. Segawa H. Haga H. Morita K. Arai H. Tatsumi S. Taketani Y. Miyamoto K. Hisano S. Fukui Y. Takeda E. J. Biochem. (Tokyo). 1997; 121: 50-55Crossref PubMed Scopus (49) Google Scholar). The of rats were 5/6 nephrectomized rats fed either the or low diet for 5/6 nephrectomized rats fed the or low diet and injected with 50 ng of 1α,25(OH)2D3/kg of bodyweight intravenously for and sham-operated rats fed normal CREA Japan) used as a Blood samples were obtained from the vena cava under ether anesthesia at day and various parameters analyzed as described above. Serum PTH was determined using a Rat PTH ELISA kit Inc., were in with for and were by the of the were expressed as and was determined using or Japan, of was of 1α,25(OH)2D3 on Serum FGF-23 in Normal administration of 1α,25(OH)2D3, three times a week for 2 dose-dependently increased serum FGF-23 however, also increased serum inorganic phosphorus Therefore, 1α,25(OH)2D3 administration increased both serum FGF-23 and serum phosphorus in normal rats. of 1α,25(OH)2D3 on Serum FGF-23 in TPTX in Thyroparathyroidectomized rats hyperphosphatemia, and also a significant in serum FGF-23 in with normal rats. Administration of 1α,25(OH)2D3 dose-dependently increased serum FGF-23 as well as serum calcium in TPTX rats. 1α,25(OH)2D3 suppressed serum inorganic phosphorus in TPTX rats. PTH to TPTX rats serum calcium, serum inorganic phosphorus, and serum FGF-23. 1α,25(OH)2D3 increased serum however, TPTX rats, significant change was in serum inorganic phosphorus and serum calcium in PTH-infused TPTX rats. These observations suggested that 1α,25(OH)2D3 increased serum FGF-23 independent of serum inorganic phosphorus and PTH. of 1α,25(OH)2D3 on Serum FGF-23 in mice kept on high calcium and high phosphorus showed low serum FGF-23 and low serum calcium in with the littermates calcium, 1α,25(OH)2D3 administration did not either serum FGF-23 or serum calcium of on Serum FGF-23 and Serum in 5/6 Nephrectomized inorganic phosphorus correlated with the dietary phosphorus in 5/6 nephrectomized rats. On the contrary, serum calcium correlated with serum phosphorus in a The 5/6 a significant increase in serum FGF-23 in rats, of the dietary phosphorus Serum FGF-23 of sham-operated rats was serum FGF-23 increased in and low diet and Serum FGF-23 showed a correlation with serum phosphorus and a correlation with serum calcium in 5/6 nephrectomized rats. However, serum FGF-23 did not correlate with serum creatinine between serum FGF-23 and serum inorganic phosphorus serum calcium and serum creatinine in 5/6 nephrectomized rats fed with 5/6 nephrectomized rats were fed either high Pi, Pi, or low diet for weeks. Serum creatinine, serum inorganic phosphorus, and serum FGF-23 were determined as described under the from of 1α,25(OH)2D3 on Serum FGF-23 and Serum in 5/6 Nephrectomized FGF-23 in the 5/6 nephrectomized rats on each diet was by the administration of 1α,25(OH)2D3 1α,25(OH)2D3 administration also increased serum inorganic phosphorus, serum calcium, and serum creatinine and serum PTH in diet not Serum inorganic phosphorus correlated with serum FGF-23 in the nephrectomized rats with or without 1α,25(OH)2D3 However, the other three parameters did not a strong correlation with serum FGF-23 between serum FGF-23 and serum inorganic phosphorus serum calcium serum creatinine and serum PTH in 5/6 nephrectomized rats with or without 1α,25-dihydroxyvitamin D3 administration. 5/6 nephrectomized rats fed were given intravenously either vehicle or 50 ng/kg 1α,25-dihydroxyvitamin D3 for weeks. Serum creatinine, serum inorganic phosphorus, and serum FGF-23 were determined as described under the from normal rats, and ng/kg 1α,25(OH)2D3 increased serum FGF-23 by and in the 5/6 nephrectomized rats, 50 ng/kg 1α,25(OH)2D3 increased serum FGF-23 by suggesting that 1α,25(OH)2D3 had a effect on increasing serum FGF-23 in rats with chronic renal failure. reported that a of 1α,25(OH)2D3 increased serum FGF-23 and suggested the increase in FGF-23 by 1α,25(OH)2D3 was independent of serum inorganic phosphorus (25Shimada T. Hasegawa H. Yamazaki Y. Muto T. Hino R. Takeuchi Y. Fujita T. Nakahara K. Fukumoto S. Yamashita T. J. Bone Miner. Res. 2004; 19: 429-435Crossref PubMed Scopus (1442) Google Scholar). We their that administration of 1α,25(OH)2D3 dose-dependently increased serum FGF-23 However, we also an increase in serum inorganic phosphorus was a strong significant correlation between serum FGF-23 and serum phosphorus in the normal rats given 1α,25(OH)2D3 intestinal phosphate uptake and suppresses PTH this indicated that 1α,25(OH)2D3 increased serum FGF-23 as well as serum evaluate the effect of 1α,25(OH)2D3 from serum phosphorus on FGF-23 1α,25(OH)2D3 was administered to thyroparathyroidectomized rats with or without PTH 1α,25(OH)2D3 also increased serum FGF-23 in and the effect was independent of serum phosphorus The direct effect of 1α,25(OH)2D3 on FGF-23 production was by the that mice did not respond to the 1α,25(OH)2D3 administration. Larsson T. Nisbeth U. Ljunggren Ö. Jüppner H. Jonsson K.B. Kidney Int. 2003; 64: 2272-2279Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar) reported phosphate deprivation and/or phosphate loading to normal did not serum however, serum phosphorus correlated with serum FGF-23 in patients with chronic kidney disease. Recent studies also that serum FGF-23 was elevated in patients with renal disease (16Webber T.J. Liu S. Indridason O.S. Quarles L.D. J. Bone Miner. Res. 2003; 18: 1227-1234Crossref PubMed Scopus (310) Google Scholar, 20Shigematsu T. Kazama J.J. Yamashita T. Fukumoto S. Hosoya T. Geyjo F. Fukagawa M. Am. J. Kidney Dis. 2004; 44: 250-256Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, T. Handa Y. Uematsu Y. Takeda S. Sekine K. Yoshihara Y. Kawakami T. Arioka K. Sato H. Uchiyama Y. Masushige S. Fukamizu A. Matsumoto T. Kato S. Nat. Genet. 1997; 6: 391-396Crossref Scopus (1001) Google Scholar). the present we investigated the effect of dietary phosphorus on FGF-23 production using 5/6 nephrectomized rats fed the with various kinds of phosphorus Serum FGF-23 was elevated in uremic however, serum FGF-23 did not correlate with serum creatinine in rats as was in human Serum phosphorus was well controlled by the dietary phosphorus in 5/6 nephrectomized rats Serum FGF-23 correlated with serum phosphorus in rats the a high serum phosphorus suppresses 1α,25(OH)2D3 production in kidney. Thus, the elevation of serum FGF-23 by a high diet was independent of serum serum FGF-23 was elevated by 1α,25(OH)2D3 administration in 5/6 nephrectomized rats fed with various However, serum FGF-23 did not correlate with serum calcium, serum creatinine, or serum PTH in rats These observations suggested that FGF-23 production was mainly by serum phosphorus and serum Recent studies (16Webber T.J. Liu S. Indridason O.S. Quarles L.D. J. Bone Miner. Res. 2003; 18: 1227-1234Crossref PubMed Scopus (310) Google Scholar, 17Jonsson K.B. Zahradnik R. Larsson T. White K.E. Sugimoto T. Imanishi Y. Yamamoto T. Hampson G. Koshiyama H. Ljuggren Ö. Oba K. Yang I.M. Miyauchi A. Econs M.J. Lavigne J. Jüppner H. N. Eng. J. Med. 2003; 348: 1656-1663Crossref PubMed Scopus (784) Google Scholar) reported that FGF-23 was elevated in patients with Serum phosphorus were correlated with circulating FGF-23 levels in patients with FGF-23 mRNA expression was in the and bones of which is a homologue of human XLH (13Liu S. Guo R. Simpson L.G. Xian Z-S. Burnham C.E. Quarles L.D. J. Biol. Chem. 2003; 278: 37419-37426Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). in PHEX, a phosphate-regulating gene with to on the are for mRNA is expressed in and 1α,25(OH)2D3 mRNA and protein in from mouse as well as a mouse in B. Desbarats M. Endocrinology. 1999; PubMed Google Scholar). mRNA expression in was suppressed by 1α,25(OH)2D3 administration in 5/6 nephrectomized rats in vivo Am. J. Physiol. 2004; PubMed Scopus Google Scholar). is that administration of 1α,25(OH)2D3 circulating FGF-23 levels in 5/6 nephrectomized rats at by of expression in FGF-23 induces by both renal and intestinal absorption by suppressing and production (3Shimada T. Mizutani S. Muto T. Yoneya T. Hino R. Takeda S. Takeuchi Y. Fujita T. Fukumoto S. Yamashita T. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6500-6505Crossref PubMed Scopus (1231) Google Scholar, T. Muto T. Urakawa I. Yoneya T. Yamazaki Y. Okawa K. Takeuchi Y. Fujita T. Fukumoto S. Yamashita T. Endocrinology. 2002; 143: 3179-3182Crossref PubMed Scopus (387) Google Scholar, 21Saito H. Kusano K. Kinosaki M. Ito H. Hirata M. Segawa H. Miyamoto K. Fukushima N. J. Biol. Chem. 2003; 278: 2206-2211Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 22Bai X.Y. Miao D. Goltzman D. Karaplis A.C. J. Biol. Chem. 2003; 278: 9843-9849Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, T. Hasegawa H. Yamazaki Y. Muto T. Hino R. Takeuchi Y. Fujita T. Nakahara K. Fukumoto S. Yamashita T. J. Bone Miner. Res. 2004; 19: 429-435Crossref PubMed Scopus (1442) Google Scholar). FGF-23 also 1α,25(OH)2D3 production in renal proximal which in the of intestinal absorption and PTH On the contrary, 1α,25(OH)2D3 an increase in circulating FGF-23, and also of vitamin D in mice to very low serum FGF-23. 5/6 nephrectomized rats, serum phosphorus controlled by dietary phosphorus content correlated with serum FGF-23, suggesting an increase in serum phosphorus induces FGF-23 production. We that a feedback loop between serum phosphorus, 1α,25(OH)2D3, and FGF-23, in which the novel phosphate-regulating bone-kidney axis be integrated with the parathyroid hormone-vitamin D3 axis in regulating phosphate homeostasis. We and for their We also for with