Pediatr Nephrol (2008) 23:1203–1210 Table 1 The pathophysiology of disorders of phosphate homeostasis associated with altered phosphatonin production/circulating concentrations Clinical phenotype Pathophysiology 1206 Clinical disorder Hypophosphatemic disorders Tumor-induced osteomalacia (TIO) X-linked hypophosphatemic rickets (XLH) Autosomal dominant hypophosphatemic rickets (ADHR) Autosomal recessive hypophosphatemia (ARHP) Hyperphosphatemic disorders Tumoral calcinosis Renal failure Hypophosphatemia, hyperphosphaturia, reduced 1α,25(OH)2D concentrations or inappropriately normal 1α,25(OH)2D concentrations for the level of serum phosphate, osteomalacia or mineralization defect As in TIO As in TIO As in TIO Hyperphosphatemia, hypophosphaturia, elevated or normal 1α,25(OH)2D concentrations, ectopic calcification Hyperphosphatemia, hypophosphaturia, reduced 1α,25(OH)2D concentrations Excess of production of phosphatonins—FGF-23, sFRP-4, MEPE, FGF-7 [10, 25, 50, 53, 78] Mutations in the endopeptidase PHEX that result in increased concentrations of FGF-23, sFRP-4 and MEPE [29, 51, 58, 79] Mutations in the FGF-23 gene that result in the formation of a mutant form of FGF-23 that is resistant to proteolysis [16] Mutations in the gene for DMP-1; associated with elevated concentrations of FGF-23 [14, 17] Mutations in the genes for Ga1NAc transferase 3 (GALNT3), FGF-23, and Klotho [18–24, 67, 80]. Some patients with GALNT3 and FGF-23 mutations have diminished concentrations of intact FGF-23. The one patient with a Klotho mutation had very high FGF-23 concentrations. Elevated FGF-23 and FGF-7 concentrations FGF-23 mice have decreased bone mineral density, elevated plasma Pi and 1α,25(OH)2D3 concentrations and low PTH concentrations [30]. It is difficult to ascertain if the decreased bone mineralization is a direct effect of reduced FGF-23 or a consequence of elevated Pi and 1α,25 (OH)2D3 concentrations. Ectopic calcification in FGF-23 mice is greatly diminished by either ablation of the vitamin D receptor or by feeding the mice a low phosphate diet, suggesting that elevated calcium and phosphate levels are important in the formation of ectopic mineral deposits [31, 32]. Transgenic mice over-expressing FGF-23 have reduced plasma Pi concentration, phosphaturia and reduced renal sodium phosphate cotransporter [33]. FGF-23 interacts with FGF receptors that belong to type 1 transmembrane phosphotyrosine kinase receptors to elicit a biological response in tissues [34]. Recent studies indicate that FGF-23 also requires Klotho, as a co-factor for receptor activation [34, 35]. In the mouse and human, the klotho/Klotho gene encodes a single-pass membrane protein which has homologies to β-glucosidases [36–39]. Two transcripts formed through alternative RNA splicing are transcribed from the gene and encode a membrane or secreted klotho protein [36]. A circulating and cerebrospi- nal fluid (CSF) form of klotho is also formed as a result of the cleavage of the membrane-bound form of the protein [36, 40]. Klotho is expressed in several tissues, including the kidney, reproductive tissues and brain [38]. The role of Klotho as a FGF-23 co-receptor is supported by the fact that Klotho-deficient mice have a phenotype similar to that of FGF-23 mice [37]. The presence of FGF-23 in the circulation of healthy human subjects suggests that it plays a role in the maintenance of Pi homeostasis. In humans, short-term alterations in dietary Pi intake do not alter FGF-23 con- centrations [41], and long-term changes in Pi intake have modest or no effect on FGF-23 concentrations [42, 43]. In animals FGF-23 concentrations are suppressed by low Pi diets and are stimulated by high Pi diets [44, 45]. In the short term, however, in rats there are no changes in FGF-23 or sFRP-4 concentrations following increases in intestinal Pi [9]. Serum FGF-23 concentrations increase following the administration of exogenous 1α,25(OH)2D3 [46], and FGF- 23 expression is increased in bone cells following 1α,25 (OH)2D3 treatment [47]. It is possible that the resultant increase in serum Pi concentrations after the administration of 1α,25(OH)2D3 stimulates the release of FGF-23, which, in turn, reduces serum Pi by promoting phosphaturia (Fig. 6). In hyperphosphatemic states, elevated Pi and FGF-23 concentrations may jointly inhibit formation of 1α,25(OH)2D3.