FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis

Shimada, Takashi; Hasegawa, Hisashi; Yamazaki, Yuji; Muto, Takanori; Hino, Rieko; Takeuchi, Yasuhiro; Fujita, Toshiro; Nakahara, Kazuhiko; Fukumoto, Seiji; Yamashita, Takeyoshi

Affiliations

¹Pharmaceutical Research Laboratories, KIRIN Brewery Co., Ltd., Takasaki, Gunma, Japan

²Department of Medicine, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan

³Department of Laboratory Medicine, University of Tokyo Hospital, Bunkyo-ku,Tokyo, Japan

Abstract and keywords

We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism.

Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)₂D] level. However, there is no clear understanding of how FGF-23 causes these changes.

Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals.

Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)₂D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)₂D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1α-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h.

Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)₂D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.

Keywords: FGF-23; phosphatonin; phosphate metabolism; vitamin D metabolism; type IIa sodium-phosphate cotransporter

Links

DOI: 10.1359/JBMR.0301264

PubMed: 15040831

WoS: 000189249000011

History

Received: 2003-05-29

Revised: 2003-08-05

Accepted: 2003-10-10

Online: 2003-12-29

Cited By (23)

Year	Entry
2020	Menon LP, Weinstein RS. Iron replacement ameliorates hypophosphatemia in autosomal dominant hypophosphatemic rickets: a review of the role of iron. Bone. February 2020;131:115137.
2020	Liu C, Pang Q, Jiang Y, Xia Y, Fang L, Wang O, Li M, Xing X, Gong Y, Xia W. Defective O-glycosylation of novel FGF23 mutations in a Chinese family with hyperphosphatemic familial tumoral calcinosis. Bone. August 2020;137:115401.
2021	Barratt KR, Sawyer RK, Atkins GJ, St-Arnaud R, Anderson PH. Vitamin d supplementation improves bone mineralisation independent of dietary phosphate in male X-linked hypophosphatemic (Hyp) mice. Bone. February 2021;143:115767.
2021	Yokomoto-Umakoshi M, Umakoshi H, Miyazawa T, Ogata M, Sakamoto R, Ogawa Y. Investigating the causal effect of fibroblast growth factor 23 on osteoporosis and cardiometabolic disorders: a Mendelian randomization study. Bone. February 2021;143:115777.
2022	Carpenter KA, Davison R, Shakthivel S, Anderson KD, Ko FC, Ross RD. Sclerostin antibody improves phosphate metabolism hormones, bone formation rates, and bone mass in adult Hyp mice. Bone. January 2022;154:116201.
2023	Liu C, Ni X, Zhao Z, Qi W, Jiang Y, Li M, Wang O, Xing X, Xia W. Bone characteristics of autosomal dominant hypophosphatemic rickets patients. Bone. February 2023;167:116602.
2021	Peacock M. Phosphate metabolism in health and disease. Calcif Tiss Int. January 2021;108(1):3-15.
2021	Koumakis E, Cormier C, Roux C, Briot K. The causes of hypo- and hyperphosphatemia in humans. Calcif Tiss Int. January 2021;108(1):41-73.
2021	Ito N, Fukumoto S. Congenital hyperphosphatemic conditions caused by the deficient activity of FGF23. Calcif Tiss Int. January 2021;108(1):104-115.
2021	Florenzano P, Hartley IR, Jimenez M, Roszko K, Gafni RI, Collins MT. Tumor-induced osteomalacia. Calcif Tiss Int. January 2021;108(1):128-142.
2021	Santos F, Díaz-Anadón L, Ordóñez FA, Haffner D. Bone disease in CKD in children. Calcif Tiss Int. April 2021;108(4):423-438.
2011	Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to x-linked hypophosphatemia. J Bone Miner Res. July 2011;26(7):1381-1388.
2020	Carpenter KA, Ross RD. Sclerostin antibody treatment increases bone mass and normalizes circulating phosphate levels in growing Hyp mice. J Bone Miner Res. March 2020;35(3):596-607.
2020	Smith PS, Gottesman GS, Zhang F, Cook F, Ramirez B, Wenkert D, Wollberg V, Huskey M, Mumm S, Whyte MP. X‐linked hypophosphatemia: uniquely mild disease associated with PHEX 3′‐UTR mutation c.231A>G (a retrospective case–control study). J Bone Miner Res*. May 2020;35(5):920-931.
2021	Roszko KL, Brown S, Pang Y, Huynh T, Zhuang Z, Pacak K, Collins MT. C‐terminal, but not intact, FGF23 and EPO are strongly correlatively elevated in patients with gain‐of‐function mutations in HIF2A: clinical evidence for EPO regulating FGF23. J Bone Miner Res. February 2021;36(2):315-321.
2021	Noonan ML, Ni P, Agoro R, Sacks SA, Swallow EA, Wheeler JA, Clinkenbeard EL, Capitano ML, Prideaux M, Atkins GJ, Thompson WR, Allen MR, Broxmeyer HE, White KE. The HIF-PHI BAY 85-3934 (Molidustat) improves anemia and is associated with reduced levels of circulating FGF23 in a CKD mouse model. J Bone Miner Res. June 2021;36(6):1117-1130.
2022	Aljuraibah F, Bacchetta J, Brandi ML, Florenzano P, Javaid MK, Mäkitie O, Raimann A, Rodriguez M, Siggelkow H, Tiosano D, Vervloet M, Wagner CA. An expert perspective on phosphate dysregulation with a focus on chronic hypophosphatemia. J Bone Miner Res. January 2022;37(1):12-20.
2022	Ovejero D, Hartley IR, Diaz LFdC, Theng E, Li X, Gafni RI, Collins MT. PTH and FGF23 exert interdependent effects on renal phosphate handling: evidence from patients with hypoparathyroidism and hyperphosphatemic familial tumoral calcinosis treated with synthetic human PTH 1–34. J Bone Miner Res. February 2022;37(2):179-184.
2022	Hidaka N, Koga M, Kimura S, Hoshino Y, Kato H, Kinoshita Y, Makita N, Nangaku M, Horiguchi K, Furukawa Y, Ohnaka K, Inagaki K, Nakagawa A, Suzuki A, Takeuchi Y, Fukumoto S, Nakatani F, Ito N. Clinical challenges in diagnosis, tumor localization and treatment of tumor-induced osteomalacia: outcome of a retrospective surveillance. J Bone Miner Res. August 2022;37(8):1479-1488.
2022	Stürznickel J, Heider F, Delsmann A, Gödel M, Grünhagen J, Huber TB, Kornak U, Amling M, Oheim R. Clinical spectrum of hereditary hypophosphatemic rickets with hypercalciuria (HHRH). J Bone Miner Res. August 2022;37(8):1580-1591.
2021	Liu C, Li X, Zhao Z, Chi Y, Cui L, Zhang Q, Ping F, Chai X, Jiang Y, Wang O, Li M, Xing X, Xia W. Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets. Osteoporos Int. April 2021;32(4):737-745.
2019	Tang JCY. Methods for the Measurement of Vitamin D Metabolites and Studies on Their Relationships in Health and Disease [PhD thesis]. University of East Anglia; 2019.
2007	Lu Y. Studies of Dentin Matrix Protein 1 (DMP1) Regulation and Function in Vivo [PhD thesis]. University of Missouri–Kansas City; 2007.