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01-07-2009 | Review Article

Hypophosphatemia: the common denominator of all rickets

Authors: Dov Tiosano, Ze’ev Hochberg

Published in: Journal of Bone and Mineral Metabolism | Issue 4/2009

Abstract

Rickets is a disease of the hypertrophic chondrocytes in the growth plate and is caused by hypophosphatemia—a derived defect in terminal chondrocyte apoptosis. This highlights the critical role of phosphorous in cartilage and bone metabolism. This review shows the role of phosphorous metabolism, transport and function in maintaining phosphorous supply to the growth plate, bone osteoblast and the kidney. Given that phosphorous is the common denominator of all rickets, this review proposes a new classification for the differential diagnosis of rickets, which is based on the mechanisms leading to hypophosphatemia—high PTH activity, high FGF23 activity or renal phosphaturia.

Dunn PM (1998) Francis Glisson (1597–1677) and the “discovery” of rickets. Arch Dis Child Fetal Neonatal Ed 78:F154–F155PubMedCrossRef

Hochberg Z (2003) Rickets–past and present: introduction. Endocr Dev 6:1–13PubMedCrossRef

Rajakumar K (2003) Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective. Pediatrics 112:e132–e135PubMedCrossRef

Faser D, Geiorge RE, Munn JD, Salter PE, Jahn R, Liu E (1957) The introduction of in vitro and in vivo calcifications in bones of children suffering from vitamin D-resistance rickets without recourse to large doses of vitamin. D Am J Dis Child 93:84

Hochberg Z, Tiosano D, Even L (1992) Calcium therapy for calcitriol-resistant rickets. J Pediatr 121:803–808PubMedCrossRef

Yoshizawa 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 (1997) Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16:391–396PubMedCrossRef

Amling M, Priemel M, Holzmann T, Chapin K, Rueger JM, Baron R, Demay MB (1999) Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology 140:4982–4987PubMedCrossRef

Sabbagh Y, Carpenter TO, Demay MB (2005) Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci USA 102:9637–9642PubMedCrossRef

Tiosano ZH D (2008) Growth disorders—pathophysiology and treatment, 2nd edn. Hodder Arnold Ltd, London

10.

Mansfield K, Rajpurohit R, Shapiro IM (1999) Extracellular phosphate ions cause apoptosis of terminally differentiated epiphyseal chondrocytes. J Cell Physiol 179:276–286PubMedCrossRef

11.

Mansfield K, Teixeira CC, Adams CS, Shapiro IM (2001) Phosphate ions mediate chondrocyte apoptosis through a plasma membrane transporter mechanism. Bone 28:1–8PubMedCrossRef

12.

Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326(Pt 1):1–16PubMed

13.

Hochberg Z, Benderli A, Levy J, Vardi P, Weisman Y, Chen T, Feldman D (1984) 1,25-Dihydroxyvitamin D resistance, rickets, and alopecia. Am J Med 77:805–811PubMedCrossRef

14.

Chagin AS, Karimian E, Zaman F, Takigawa M, Chrysis D, Savendahl L (2007) Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones. Bone 40:1415–1424PubMedCrossRef

15.

Murer H, Hernando N, Forster I, Biber J (2000) Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev 80:1373–1409PubMed

16.

Busch AE, Schuster A, Waldegger S, Wagner CA, Zempel G, Broer S, Biber J, Murer H, Lang F (1996) Expression of a renal type I sodium/phosphate transporter (NaPi-1) induces a conductance in Xenopus oocytes permeable for organic and inorganic anions. Proc Natl Acad Sci USA 93:5347–5351PubMedCrossRef

17.

Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS (1998) Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci USA 95:5372–5377PubMedCrossRef

18.

Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, Tatsumi S, Miyamoto K (2002) Growth-related renal type II Na/Pi cotransporter. J Biol Chem 277:19665–19672PubMedCrossRef

19.

Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J (1998) Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci USA 95:14564–14569PubMedCrossRef

20.

Bai L, Collins JF, Ghishan FK (2000) Cloning and characterization of a type III Na-dependent phosphate cotransporter from mouse intestine. Am J Physiol Cell Physiol 279:C1135–C1143PubMed

21.

Yoshiko Y, Candeliere GA, Maeda N, Aubin JE (2007) Osteoblast autonomous Pi regulation via Pit1 plays a role in bone mineralization. Mol Cell Biol 27:4465–4474PubMedCrossRef

22.

Virkki LV, Biber J, Murer H, Forster IC (2007) Phosphate transporters: a tale of two solute carrier families. Am J Physiol Renal Physiol 293:F643–F654PubMedCrossRef

23.

Hochberg ZTD (2004) Abnormalities of calcium and parathyroid hormone. Lippincott Williams and Wilkins, Philadelphia

24.

Quarles LD (2008) Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118:3820–3828PubMedCrossRef

25.

Rizzoli R, Fleisch H, Bonjour JP (1977) Role of 1,25-dihydroxyvitamin D3 on intestinal phosphate absorption in rats with a normal vitamin D supply. J Clin Invest 60:639–647PubMedCrossRef

26.

Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA (2005) Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146:5358–5364PubMedCrossRef

27.

Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, Gabizon D, Liberman UA (1985) Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 312:611–617PubMedCrossRef

28.

Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H (2006) SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet 78:179–192PubMedCrossRef

29.

Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R, Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM (2006) Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet 78:193–201PubMedCrossRef

30.

Beck GR Jr (2003) Inorganic phosphate as a signalling molecule in osteoblast differentiation. J Cell Biochem 90:234–243PubMedCrossRef

31.

Beck GR Jr, Moran E, Knecht N (2003) Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2. Exp Cell Res 288:288–300PubMedCrossRef

32.

Beck GR Jr, Zerler B, Moran E (2000) Phosphate is a specific signal for induction of osteopontin gene expression. Proc Natl Acad Sci USA 97:8352–8357PubMedCrossRef

33.

Meleti Z, Shapiro IM, Adams CS (2000) Inorganic phosphate induces apoptosis of osteoblast-like cells in culture. Bone 27:359–366PubMedCrossRef

34.

Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568PubMed

35.

Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Juppner H, Lanske B (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23:421–432PubMedCrossRef

36.

Yamashita H, Yamazaki Y, Hasegawa H, Yamashita T, Fukumoto S, Shigematsu T, Kazama JJ, Fukagawa M, Noguchi S (2007) Fibroblast growth factor-23 (FGF23) in patients with transient hypoparathyroidism: its important role in serum phosphate regulation. Endocr J 54:465–470PubMedCrossRef

37.

Antoniucci DM, Yamashita T, Portale AA (2006) Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 91:3144–3149PubMedCrossRef

38.

Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB (2003) 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 64:2272–2279PubMedCrossRef

39.

Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar S, Martin TJ, Onyia JE (2001) Catabolic effects of continuous human PTH (1–38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 142:4047–4054PubMedCrossRef

40.

Holick MF (2006) Resurrection of vitamin D deficiency and rickets. J Clin Invest 116:2062–2072PubMedCrossRef

41.

Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 101:7711–7715PubMedCrossRef

42.

Mawer EB, Stanbury W, Robinson MJ, James J, Close C (1986) Vitamin D nutrition and vitamin D metabolism in the premature human neonate. Clin Endocrinol (Oxf) 25:641–649CrossRef

43.

DeLucia MC, Mitnick ME, Carpenter TO (2003) Nutritional rickets with normal circulating 25-hydroxyvitamin D: a call for re-examining the role of dietary calcium intake in North American infants. J Clin Endocrinol Metab 88:3539–3545PubMedCrossRef

44.

Baroncelli GI, Bereket A, El Kholy M, Audi L, Cesur Y, Ozkan B, Rashad M, Fernandez-Cancio M, Weisman Y, Saggese G, Hochberg Z (2008) Rickets in the Middle East: role of environment and genetic predisposition. J Clin Endocrinol Metab 93:1743–1750PubMedCrossRef

45.

Menon PS, Madhavi N, Mukhopadhyaya S, Padhy AK, Bal CS, Sharma LK (1994) Primary hyperparathyroidism in a 14 year old girl presenting with bone deformities. J Paediatr Child Health 30:441–443PubMedCrossRef

46.

Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 98:6500–6505PubMedCrossRef

47.

Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK (2005) 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–G1042PubMedCrossRef

48.

Garringer HJ, Malekpour M, Esteghamat F, Mortazavi SM, Davis SI, Farrow EG, Yu X, Arking DE, Dietz HC, White KE (2008) Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis. Am J Physiol Endocrinol Metab 295:E929–E937PubMedCrossRef

49.

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 (2004) Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36:579–581PubMedCrossRef

50.

Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117:2684–2691PubMedCrossRef

51.

Bai XY, Miao D, Goltzman D, Karaplis AC (2003) The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 278:9843–9849PubMedCrossRef

52.

Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD (2006) Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291:E38–E49PubMedCrossRef

53.

Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD (2003) Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 278:37419–37426PubMedCrossRef

54.

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 (2006) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38:1248–1250PubMedCrossRef

55.

Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P (2003) FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 112:683–692PubMed

56.

Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H (2003) Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348:1656–1663PubMedCrossRef

57.

Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R (2003) Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest 112:785–794PubMed

58.

Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP (2008) A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci USA 105:3455–3460PubMedCrossRef

59.

Hafner C, Hartmann A, Vogt T (2007) FGFR3 mutations in epidermal nevi and seborrheic keratoses: lessons from urothelium and skin. J Invest Dermatol 127:1572–1573PubMedCrossRef

60.

Heike CL, Cunningham ML, Steiner RD, Wenkert D, Hornung RL, Gruss JS, Gannon FH, McAlister WH, Mumm S, Whyte MP (2005) Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis? Am J Med Genet A 139A:67–77 PubMedCrossRef

61.

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 (2005) Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76:361–367PubMedCrossRef

62.

Fisher SE, Black GC, Lloyd SE, Hatchwell E, Wrong O, Thakker RV, Craig IW (1994) Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent’s disease (an X-linked hereditary nephrolithiasis). Hum Mol Genet 3:2053–2059PubMed

63.

Levtchenko EN, Monnens LA, Bokenkamp A, Knoers NV (2007) From gene to disease: Dent’s disease caused by abnormalities in the CLCN5 and OCRL1 genes. Ned Tijdschr Geneeskd 151:2377–2380PubMed

Title: Hypophosphatemia: the common denominator of all rickets
Authors: Dov Tiosano
Ze’ev Hochberg
Publication date: 01-07-2009
Publisher: Springer Japan
Published in: Journal of Bone and Mineral Metabolism / Issue 4/2009
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI: https://doi.org/10.1007/s00774-009-0079-1

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