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NDT Advance Access originally published online on March 29, 2007
Nephrology Dialysis Transplantation 2007 22(6):1521-1523; doi:10.1093/ndt/gfm116
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

More on the bone-kidney axis—lessons from hypophosphataemia*

Sagrario Cañadillas1, Alberto Rodríguez-Benot1 and Mariano Rodríguez1

1Research Unit and Nephrology Service, Hospital Universitario Reina Sofía, Cordoba, Spain

Correspondence and offprint requests to: Mariano Rodriguez, Unidad de Investigación, Hospital Universitario Reina Sofía, Avenida Menendez Pidal s/n. 14004 Córdoba. Spain. Email: juanm.rodriguez.sspa{at}juntadeandalucia.es

Keywords: high fibroblast growth factor (FGF23); hypophosphataemia; phosphaturia; dentin matrix protein 1 (DMP1)



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There are several hypophosphataemic disorders attributed to the phosphaturic effect of high fibroblast growth factor (FGF23) levels (Table 1). X-linked hypophosphatemia (XLH) is caused by inactivating mutations in a gene encoding a putative endopeptidase (PHEX) which normally cleaves the phosphaturic hormone FGF23 [1]. Both PHEX and FGF23 are abundantly expressed in bone. Inactivation of PHEX leads to excess of FGF23 which in turn causes phosphaturia, hypophosphataemia and inappropriately normal levels of 1,25(OH)2 D3 that should be high due to the hypophosphataemic stimulus of renal 1{alpha} hydroxylase activity. Autosomal dominant hypophosphataemic rickets (ADHR) are caused by mutations in the FGF23 gene that makes this phosphaturic factor resistant to proteolytic cleavage by a proprotein convertase [2]. High FGF23 is also observed in patients with certain mesenchymal tumours in which FGF23 is overproduced and secreted inducing hypophosphataemia and osteomalacia (TIO) [3].


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  		Table 1. Hypophosphataemic disorders associated with increased serum FGF23 levels

 
There are patients with autosomal recessive hypophosphataemic rickets (ARHR) whose clinical features are similar to ADHR and XLH but with autosomal recessive inheritance. The recently published study by Lorenz-Depiereux et al. [4] describes mutations in dentin matrix protein (DMP1), located on chromosome 4q21 [PDB] , in eight ARHR patients from three different families. All affected individuals were homozygous for the mutated allele and parents were heterozygous for the respective mutation. Affected patients had renal phosphate wasting, rachitic bone deformities and in one patient, a bone biopsy revealed osteomalacia. Intact FGF23 levels were available in four individuals and values were high or close to upper limit of normal; these patients were receiving calcitriol and oral phosphate supplements that may stimulate FGF23 production.



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It is clear that the classical PTH/vitamin D axis do not fully account for the complexity of renal phosphate handling and skeletal mineralization. A growing body of evidence suggests that other factors of bone origin participate in maintaining phosphate homeostasis, such as FGF23, matrix extracellular phosphoglycoprotein (MEPE) and frizzled-related protein 4. These factors known collectively as phosphatonins [5], have been shown to be associated with hypophosphataemia. Only FGF23 is involved in XLH, ADHP and TIO. The study by Lorenz-Depiereux shows that FGF23 may also mediate renal phosphate wasting in ARHP.

There is high expression of FGF23 mRNA in bone [6] although it has been identified in many other tissues. Circulating levels of FGF23 are increased by high dietary phosphate, elevated serum phosphate and by administration of 1.25(OH)2 D3 [7–10]. FGF23 administration to animals induces a decrease in serum phosphate levels and phosphaturia accompanied by a reduction in renal mRNA and protein levels of the phosphate transporter NaPi-2a and a decrease in renal mRNA in 1{alpha} hydroxylase [3,8,11]. Lack of FGF23 expression in null mice results in an increased circulating level of 1.25(OH)2 D3 despite hyperphosphatemia, hypercalcaemia and low PTH levels [12]. The presence of FGF23 prevents undesirable hyperphosphataemia when PTH and calcitriol are increased in response to hypocalcaemia. Both calcium and phosphate absorption from the intestine are activated by 1.25(OH)D3, with the former correcting hypocalcemia but the latter possibly eliciting hyperphosphataemia. Initially this hyperphosphataemia could be compensated for by PTH-induced phosphaturia although this effect is only temporary because restoration of calcium will suppress PTH. Thus, stimulation of FGF23 by 1,25(OH)2 D3 and hyperphosphataemia provides a protection against undesirable hyperphosphataemia potentially associated with the restoration of calcium levels.

Dentin matrix protein 1 (DMP1) first discovered by George et al. [13], belongs to a family of bone non-collagenous matrix proteins called SIBLING (small integrin-binding ligand, N-linked glycoprotein). Other members of this family are dentin sialophosphoprotein (DSPP), integrin-binding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein (MEPE) and osteopontin (also named secreted phosphoprotein 1, SPP1). These proteins are believed to play key biological roles in the mineralization of bone and dentin and it is clear that some functions of the SIBLING family members are dependent on the nature and extent of post-translational modifications that would result in significant changes in protein structure. DMP1 is processed at four different cleavage sites and can be achieved by BMP1/tolloid-like proteinases in vitro [14]. The roles of DMP1 in mineralization are supported by observations that transgenic MC3T3-E1 cells overexpressing DMP1 show earlier onset of mineralization and produce mineralized nodules of significantly larger sizes when compared with the non-transgenic cells [15]. In DMP1 knockout mice there is delayed conversion of osteoid to bone and predentin to dentin occurs at three weeks, and this condition is more severe by three months. [16, 17]. Elegant in vitro studies demonstrate the key role of DMP1 in regulating the transformation of amorphous calcium phosphate to crystalline hydroxyapatatite [18].

The recent study by Feng et al. [17] published in the same issue of Nature Genetics as the one by Lorenz-Depiereux [4], describes four individuals from two different families with ARHR who have mutations in the DMP1 gene with clinical characteristics similar to those presented by patients in the article by Lorenz-Depiereux [4]. Feng et al. also describe the findings on the DMP1-null mouse in which the mineralization defect is associated with severe hypophosphataemia, phosphaturia and increased FGF23 levels. DMP1 is highly expressed in osteocytes [19], and the authors suggest that the lack of DMP1 causes defective osteoblast maturation and differentiation into osteocytes. Hypophosphataemia itself causes mineralization the defect which is one of the most prominent defects in DMP1-null mice. The question is how much of the mineralization defect is secondary to hypophosphataemia; the administration of a high phosphate diet corrected the mineralization defect at the level of the growth plate, however, only partial resolution of osteomalacia was observed suggesting that ricket features are secondary to hypophosphataemia and, for the most part, osteomalacia is due to the lack of DMP1 on osteocytes. Thus, DMP1 has both direct effects on osteocytes and indirect effects through hypophosphataemia on mineralization.

Recently, Narayanan et al. [20] showed that, in addition to its role in the regulation of mineral formation, DMP1 may act as a transcriptional component for the activation of osteoblast-specific genes like osteocalcin (Figure 1).


Figure 1
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  		Fig. 1. (Modified from Narayanan et al. [20]. Represents the hypothetical model of the export of DMP1 from the nucleus to the extracellular matrix in a differentiating osteoblast. The phosphates present at the time of calcified tissue formation can trigger the intracellular calcium stores to release calcium. The released calcium gets transported to the nucleus either by an unknown carrier protein or through the IP3/ryanodine receptors on the nuclear membrane. In the nucleus, calcium binds to DMP1, which undergoes structural modification (I). Casein kinase II then phosphorylates DMP1, leading to a conformational change that exposes the nuclear export signal sequence (II). This triggers the export of the DMP1-Ca2+ complex to the extracellular matrix where the phosphorylated, highly anionic DMP1 initiates the nucleation of hydroxyapatite formation.

 
That inactivating mutation of DMP1 causes mineralization defects is easy to understand, however the link between a DMP1 mutation and elevation of FGF23 serum levels is unknown. It is not unreasonable to hypothesize that the mineralization process, and therefore the need for phosphate at the bone level, may participate in the control of body phosphate. In theory a mineralization defect with a low phosphate uptake by bone may result in hyperphosphatemia; FGF23-induced phosphaturia would then prevent extraosseous phosphate and calcium deposition.



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The study by Lorenz-Depiereux demonstrates that mutations of the Dentin Matrix Protein (DMP1) cause autosomal recessive hypophosphataemic rickets (ARHR). In these patients phosphate wasting is explained by elevated FGF23 levels. Bone mineralization defects cannot be exclusively attributed to hypophosphataemia but also to the abnormal bone matrix protein. The study also suggests that bone matrix proteins and mineralization may participate in phosphate homeostasis.

Conflict of interest statement. Dr Mariano Rodriguez is a consultant for Amgen, Shire and Genzyme, and has received grants from Amgen.



   Notes
 
* Comment on Lorenz-Depiereux B et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nature Genet 2006; 3: 1248–1250 Back



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  1. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet (1995) 11:130–136.[CrossRef][ISI][Medline]
  2. The ADHR Consortium. Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23. Nat Gen (2000) 26:345–348.[CrossRef][ISI][Medline]
  3. Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA (2001) 98:6501–6505.
  4. Lorenz-Depiereux B, Bastepe M, Benet-Pagés A, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet (2006) 38:1248–1250.[CrossRef][ISI][Medline]
  5. Berndt TJ, Schiavi S, Kumar R. "Phosphatonins" and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol (2005) 289:F1170–F1182.[Abstract/Free Full Text]
  6. Liu S, Guo R, Simpson LG, et al. Regulation of fibroblast growh factor 23 expression but not degradation by PHEX. J Biol Chem (2003) 278:37419–37426.[Abstract/Free Full Text]
  7. Saito H, Maeda A, Ohtomo S, et al. Circulating FGF23 is regulated by 1 alpha, 25-dihydroxyvitamin D3 and phosphate in vivo. J Biol Chem (2005) 280:2543–2549.[Abstract/Free Full Text]
  8. Quarles LD. Evidence for a bone-kidney axis regulating phosphate homeostasis. J Clin Invest (2003) 112:642–646.[CrossRef][ISI][Medline]
  9. 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 (2005) 90:1519–1524.[Abstract/Free Full Text]
  10. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab (2006) 91:3144–3149.[Abstract/Free Full Text]
  11. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res (2004) 19:429–35.[CrossRef][ISI][Medline]
  12. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest (2004) 113:561–568.[CrossRef][ISI][Medline]
  13. George A, Sabsay B, Simolan PAL, Veis A. Characterization of a novel dentin matrix acidic phosphoprotein. J Biol Chem (1993) 268:12624–12630.[Abstract/Free Full Text]
  14. Steiglitz BM, Ayala M, Narayanan K, et al. Bone morphogenetic protein –1/Tolloid-like proteinases process dentin matrixprotein-1. J Biol Chem (2004) 279:980–986.[Abstract/Free Full Text]
  15. Narayanan K, Srinivas R, Ramachandran A, et al. Differentiation of embryonic mesenchymal cells to odontoblast-like cells by overexpression of dentin matrix protein 1. Proc Natl Acad Sci USA (2001) 98:4516–4521.[Abstract/Free Full Text]
  16. Ling Y, Rios HF, Myers ER, et al. DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis. J Bone Miner Res (2005) 20:2169–2177.[CrossRef][ISI][Medline]
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  18. Gajjeraman S Narayanan, Hao J, et al. Matrix macromolecules in hard tissues control the nucleation and hierarchical assembly of hydroxyapatite. J Biol Chem (2007) 282:1193–1204.[Abstract/Free Full Text]
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Received for publication: 29.12.06
Accepted in revised form: 9. 2.07


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