Pediatr Nephrol (2008) 23:1203–1210 1207 Fig. 6 Relationships between changes in Pi, 1α,25(OH)2D and FGF-23. Reprinted with permission [3] Secreted frizzled-related protein, fibroblast growth factor-7 and matrix extracellular phosphoglycoprotein: Like FGF-23, sFRP-4 decreases renal Pi reabsorption by reducing sodium phosphate transporters in renal proximal tubules and inhibits formation of 1α,25(OH)2D3 [25]. FGF-7 inhibits sodium-dependent Pi transport in opossum kidney cells, and anti-FGF-7 antibodies attenuate the phosphate transport inhibition induced by FGF-7 [48]. We have recently shown that FGF-7 is phosphaturic in vivo [49]. MEPE has been shown to increase the fractional excretion of phosphate and to induce hypophosphatemia in vivo [50]. In addition, MEPE inhibits bone mineralization in vitro, and MEPE mice have increased bone minerali- zation. Importantly, MEPE does not inhibit 1α,25(OH)2D3 formation. We will briefly discuss some clinical disorders in which one or more of the phosphatonins play a key role in the pathogenesis of the disease. Role of phosphatonins in clinical disorders Tumor-induced osteomalacia TIO is a syndrome due to the presence of mesenchymal tumors that is associated with hypophosphatemia, hyperphosphaturia, inappropriately low serum 1α,25(OH)2D3 concentrations and osteomalacia [10]. The resolution of these biochemical and bone abnormalities following tumor removal supports the notion of the presence of a circulating factor (phosphatonin) secreted by the tumor. Numerous reports show elevation of FGF-23 in some, but not all, patients with TIO [33, 51, 52]. Removal of the tumor is associated with reduction in serum FGF-23 concentrations, and there is a temporal association between reduction in FGF-23 concentration and elevation in serum Pi, decrease in renal Pi wasting and increase in 1α,25(OH)2D3 concentrations [33, 51, 52]. sFRP-4, MEPE and FGF-7 have also been shown to be expressed by tumors associated with TIO [25, 48, 53]. The presence of different phosphatonins in TIO points towards the complex pathogenesis of this clinical condition. X-linked hypophosphatemic rickets Patients with X-linked hypophosphatemic rickets (XLH) manifest phosphaturia, hypophosphatemia and rickets [12, 15, 54]. Parabiosis and kidney cross-transplantation experiments have shown that there is a circulating hypophosphatemic factor present in the serum of Hyp mice (the mouse homolog of human XLH) [55–57]. In XLH, there are mutations of the gene encoding the endopeptidase, PHEX [15]. Patients with XLH have elevated serum concentrations of FGF-23 [51, 58], thereby indicating that PHEX is involved in the processing of FGF- 23. Some studies have demonstrated that PHEX is respon- sible for FGF-23 degradation in vitro [26], whereas others have failed to demonstrate such an effect [59–61]. Autosomal dominant hypophosphatemic rickets Autosomal dominant hypophosphatemic rickets (ADHR) is an in- herited disorder of Pi homeostasis characterized by phos- phaturia, hypophosphatemia, osteomalacia and rickets [13]. The ADHR Consortium identified mutations in the FGF-23 gene that encodes a mutant FGF-23 protein that lacks a nor- mal furin proconvertase site making it resistant to proteolysis [16]. A long-lived stable form of FGF-23 is responsible for the clinical manifestations of this disorder [62]. Fibrous dysplasia/McCune-Albright syndrome Fibrous dys- plasia is a genetic non-inherited disease caused by somatic activating missense mutations of GNAS 1 that lead to variable clinical features, including polyostotic fibrous dysplasia, with endocrine (precocious puberty, pituitary gigantism, Cushing’s syndrome, thyrotoxicosis) and cuta- neous (pigment patches on the skin) abnormalities [63]. Pi wasting is seen in approximately 50% of these patients and is associated with defective bone mineralization. One study demonstrated that FGF-23 concentration was elevated in patients with hypophosphatemia but was not increased in patients with normal Pi concentrations [64]. It is possible that the fibrous dysplastic tissue secretes FGF-23, and that serum FGF-23 concentrations are reflective of the disease burden in these patients. Tumor calcinosis Patients with tumor calcinosis (TC) manifest hyperphosphatemia, reduced renal Pi excretion and elevated 1α,25(OH)2D3 concentrations [65]. Three different types of mutations account for this syndrome. The first type occurs in the gene Ga1NAc transferase 3 (GALNT3), which encodes a glycosyltransferase responsi- ble for initiating mucin-type O-glycosylation [18]. Some patients with this syndrome have low concentrations of intact FGF-23 but high concentrations of FGF-23 frag- ments. It has been hypothesized that these FGF-23 frag- ments lack biological activity, and, therefore, the clinical picture is consistent with what would be seen with low intact FGF-23 concentrations. In vivo infusion studies with