Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets

Journal of Bone and Mineral Research

Volumn 28, Issue 4, 2013, Pages 899-911

  Wöhrle, Simon ^a   Henninger, Christine ^a   Bonny, Olivier ^b   Thuery, Anne ^a   Beluch, Noemie ^a   Hynes, Nancy E ^c   Guagnano, Vito ^a   Sellers, William R ^d   Hofmann, Francesco ^a   Kneissel, Michaela ^a   Graus Porta, Diana ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

^b UNIVERSITY OF LAUSANNE   (Switzerland)

^c FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH   (Switzerland)

^d NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

FGF23; fibroblast growth factor receptor; hypophosphatemic rickets; phosphate homeostasis; targeted therapy

Indexed keywords

DENTIN MATRIX PROTEIN 1; FIBROBLAST GROWTH FACTOR 23; FIBROBLAST GROWTH FACTOR RECEPTOR; NVP BGJ398; PROTEIN INHIBITOR; UNCLASSIFIED DRUG; 3-(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)-1-(6-(4-(4-ETHYLPIPERAZIN-1-YL)-PHENYLAMINO)PYRIMIDIN-4-YL)-1-METHYLUREA; CARBANILAMIDE DERIVATIVE; DIHYDROXY-VITAMIN D3; DMP1 PROTEIN, MOUSE; FIBROBLAST GROWTH FACTOR; ION; MINERAL; PYRIMIDINE DERIVATIVE; SCLEROPROTEIN; VITAMIN D;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTOSOMAL RECESSIVE DISORDER; AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS; BONE GROWTH; BONE MINERALIZATION; CANCER THERAPY; CONTROLLED STUDY; EXPERIMENTAL MODEL; GROWTH PLATE; HUMAN; HYPOCALCEMIA; HYPOPHOSPHATEMIC RICKETS; MOUSE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; X LINKED HYPOPHOSPHATEMIC RICKETS; ANALOGS AND DERIVATIVES; ANATOMY AND HISTOLOGY; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; BODY WEIGHT; BONE DEVELOPMENT; C57BL MOUSE; DEFICIENCY; DRUG EFFECTS; FEMUR; HOMEOSTASIS; KIDNEY; METABOLISM; PATHOLOGY; RICKETS, HYPOPHOSPHATEMIC; TAIL;

ANIMALS; BODY WEIGHT; BONE DEVELOPMENT; EXTRACELLULAR MATRIX PROTEINS; FEMUR; FIBROBLAST GROWTH FACTORS; GROWTH PLATE; HOMEOSTASIS; IONS; KIDNEY; MICE, INBRED C57BL; MINERALS; PHENYLUREA COMPOUNDS; PYRIMIDINES; RECEPTORS, FIBROBLAST GROWTH FACTOR; RICKETS, HYPOPHOSPHATEMIC; SIGNAL TRANSDUCTION; TAIL; VITAMIN D;

EID: 84875302265     PISSN: 08840431     EISSN: 15234681     Source Type: Journal    
DOI: 10.1002/jbmr.1810     Document Type: Article

References (53)

1. Razzaque MS., The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol. 2009; 5: 611-9.
2. 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. 2004; 19: 429-35.
3. 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 U S A. 2001; 98: 6500-5.
4. Baum M, Schiavi S, Dwarakanath V, Quigley R., Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules. Kidney Int. 2005; 68: 1148-53.
5. 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. 2004; 314: 409-14.
6. 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. 2006; 444: 770-4.
7. 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. 2006; 281: 6120-3.
8. 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. 1997; 390: 45-51.
9. 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. 2004; 113: 561-8.
10. Yoshida T, Fujimori T, Nabeshima Y., Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology. 2002; 143: 683-9.
11. 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, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol. 2004; 23: 421-32.
12. The ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000; 26: 345-8.
13. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet. 1995; 11: 130-6.
14. 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. 2006; 38: 1248-50.
15. 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. 2010; 86: 273-8.
16. 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. 2010; 86: 267-72.
17. 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. 2001; 60: 2079-86.
18. 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. 2006; 38: 1310-5.
19. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD., Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab. 2006; 291: E38-49.
20. 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. 2008; 295: E254-61.
21. Nakatani T, Ohnishi M, Razzaque MS., Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J. 2009; 23: 3702-11.
22. Li H, Martin AC, David V, Quarles LD., Compound deletion of FGFR3 and FGFR4 partially rescues the Hyp mouse phenotype. Am J Physiol Endocrinol Metab. 2011 Mar; 300 (3): E508-17.
23. Liu S, Vierthaler L, Tang W, Zhou J, Quarles LD., FGFR3 and FGFR4 do not mediate renal effects of FGF23. J Am Soc Nephrol. 2008; 19: 2342-50.
24. 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. 2009; 297: F282-91.
25. Gattineni J, Twombley K, Goetz R, Mohammadi M, Baum M., Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol. 2011 Aug; 301 (2): F371-7.
26. Wohrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M, Muller M, Kinzel B, Thuery A, Brueggen J, Hynes NE, Sellers WR, Hofmann F, Graus-Porta D., FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res. 2011; 26: 2486-97.
27. Pettifor JM., What's new in hypophosphataemic rickets?. Eur J Pediatr. 2008; 167: 493-9.
28. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL., A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. 2011; 26: 1381-8.
29. Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, Jensen MR, Schnell C, Schmid H, Wartmann M, Berghausen J, Drueckes P, Zimmerlin A, Bussiere D, Murray J, Graus-Porta D., Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phe nylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011; 54: 7066-83.
30. Feng JQ, Huang H, Lu Y, Ye L, Xie Y, Tsutsui TW, Kunieda T, Castranio T, Scott G, Bonewald LB, Mishina Y., The Dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development. J Dent Res. 2003; 82: 776-80.
31. Eicher EM, Southard JL, Scriver CR, Glorieux FH., Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets. Proc Natl Acad Sci U S A. 1976; 73: 4667-1.
32. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR., Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987; 2: 595-610.
33. Wolf J, LoRusso PM, Camidge RD, Perez JM, Tabernero J, Hidalgo M, Schuler M, Tian GG, Soria JC, Delord JP, Campone M, Bachelot T, van der Noll R, Ringeisen FP, Nogova L, Sequist LV, Schellens JHM., Abstract LB-122: A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. Philadelphia: AACR; 2012; 72: (8 Suppl): LB122.
34. Strom TM, Francis F, Lorenz B, Boddrich A, Econs MJ, Lehrach H, Meitinger T., Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia. Hum Mol Genet. 1997; 6: 165-71.
35. Ranch D, Zhang MY, Portale AA, Perwad F., Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice. J Bone Miner Res. 2011; 26: 1883-90.
36. Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, Fujita T, Wada M, Yamashita T, Fukumoto S, Shimada T., Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res. 2009; 24: 1879-88.
37. 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. 2011 Aug; 25 (8): 2551-62.
38. Carpenter TO., The expanding family of hypophosphatemic syndromes. J Bone Miner Metab. 2012; 30: 1-9.
39. Sabbagh Y, Giral H, Caldas Y, Levi M, Schiavi SC., Intestinal phosphate transport. Adv Chronic Kidney Dis. 2011; 18: 85-90.
40. 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. 2007; 117: 4003-8.
41. Eswarakumar VP, Schlessinger J., Skeletal overgrowth is mediated by deficiency in a specific isoform of fibroblast growth factor receptor 3. Proc Natl Acad Sci U S A. 2007; 104: 3937-42.
42. Kim HJ, Delaney JD, Kirsch T., The role of pyrophosphate/phosphate homeostasis in terminal differentiation and apoptosis of growth plate chondrocytes. Bone. 2010; 47: 657-65.
43. Sabbagh Y, Carpenter TO, Demay MB., Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci U S A. 2005; 102: 9637-42.
44. Miedlich SU, Zhu ED, Sabbagh Y, Demay MB., The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice. Endocrinology. 2010; 151: 4607-12.
45. Zhang MY, Ranch D, Pereira RC, Armbrecht HJ, Portale AA, Perwad F., Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice. Endocrinology. 2012 Apr; 153 (4): 1806-16.
46. 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. 2010; 95: 1846-50.
47. Alon US, Clinical practice., Fibroblast growth factor (FGF)23: a new hormone. Eur J Pediatr. 2011; 170: 545-54.
48. Chefetz I, Sprecher E., Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis. Biochim Biophys Acta. 2009; 1792: 847-52.
49. Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B., An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet. 2005; 14: 385-90.
50. Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T, Yamashita T, Fukumoto S., Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. J Bone Miner Res. 2011; 26: 803-10.
51. Bergwitz C, Juppner H., FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol. 2012; 728: 41-64.
52. Bhan I, Shah A, Holmes J, Isakova T, Gutierrez O, Burnett SM, Juppner H, Wolf M., Post-transplant hypophosphatemia: tertiary 'hyper-phosphatoninism' ? Kidney Int. 2006; 70: 1486-94.
53. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John SM, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro O, Kusek JW, Keane MG, Wolf M., FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011; 121: 4393-408.