Autosomal Dominant Hypophosphatemic Rickets Research Articles

FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa

Fibroblast growth factor (FGF)-23 was identified as a causative factor of tumor-induced osteomalacia and also as a responsible gene for autosomal dominant hypophosphatemic rickets. To clarify the pathophysiological roles of FGF-23 in these diseases, we generated its transgenic mice. The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone. The renal phosphate wasting in the transgenic mice was accompanied by the reduced expression of sodium phosphate cotransporter type IIa in renal proximal tubules. These results reinforce the notion that the excessive action of FGF-23 plays a causative role in the development of several hypophosphatemic rickets/osteomalacia.

The phosphatonin pathway: New insights in phosphate homeostasis

Serum phosphate concentrations are maintained within a defined range by processes that regulate the intestinal absorption and renal excretion of inorganic phosphate. The hormones currently believed to influence these processes are parathyroid hormone (PTH) and the active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)2D). A new class of phosphate-regulating factors, collectively known as the phosphatonins, have been shown to be associated with the hypophosphatemic diseases, tumor-induced osteomalacia (TIO), X-linked hypophosphatemic rickets (XLH), and autosomal-dominant hypophosphatemic rickets (ADHR). These factors, which include fibroblast growth factor 23 (FGF23) and secreted frizzled-related protein 4 (FRP4), decrease extracellular fluid phosphate concentrations by directly reducing renal phosphate reabsorption and by suppressing 1alpha,25(OH)2D formation through the inhibition of 25-hydroxyvitamin D 1alpha-hydroxylase. The role of these substances under normal or pathologic conditions is not yet clear. For example, it is unknown whether any of the phosphatonins are directly responsible for the decreased concentrations of 1alpha,25(OH)2D observed in chronic and end-stage kidney disease or whether they are induced in an attempt to correct the hyperphosphatemia seen in late stages of chronic renal failure. Future experiments should clarify their physiologic and pathologic roles in phosphate metabolism.

Renal phosphate wasting disorders: clinical features and pathogenesis

Rickets and osteomalacia are associated with hypophosphatemia in several disease states, including X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia. Recent advances in the understanding of these diseases include discovery of mutations in the genes encoding human p hosphate-regulating gene with h omologies to e ndopeptidases on the X chromosome (PHEX) and fibroblast growth factor 23 (FGF-23) and the finding of overproduction of FGF-23 and other proteins including matrix extracellular phosphoglycoprotein (MEPE) and frizzled-related protein 4 (FRP-4) in tumor-induced osteomalacia. Research is ongoing to better define how these proteins relate to each other and to the sodium-phosphate cotransporter in both normal and abnormal phosphate metabolism. New and improved therapies for disorders of phosphate metabolism, osteomalacia, and rickets will develop as our knowledge of phosphate metabolism grows.

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

Hyperphosphatemia is a risk factor for the development of several different complications of chronic kidney disease (CKD), including secondary hyperparathyroidism and cardiovascular complications, due to the formation of calcium-phosphate deposits. Fibroblast growth factor-23 (FGF-23) is a recently discovered protein that is mutated in autosomal-dominant hypophosphatemic rickets, an inherited phosphate wasting disorder, and it may represent a novel hormonal regulator of phosphate homeostasis. We therefore hypothesized that FGF-23 levels may be altered in hyperphosphatemia associated with renal failure and that its concentration changes in response to different levels of phosphate intake. Using a two-site enzyme-linked immunosorbent assay (ELISA) detecting the C-terminal portion of FGF-23, serum concentration was measured in 20 patients with different stages of renal failure (creatinine range 155 to 724 micromol/L), in 33 patients with end-stage renal disease (ESRD) on dialysis treatment, and in 30 patients with functioning renal grafts. Furthermore, six healthy males were given oral phosphate binders in combination with low dietary phosphate intake for 2 days followed by 3 days of repletion with inorganic phosphate. FGF-23 levels were determined at multiple time points. FGF-23 serum levels were significantly elevated in CKD with a strong correlation between serum creatinine and FGF-23 concentration. Independent correlations were also seen between FGF-23 and phosphate, calcium, parathyroid hormone (PTH), and 1,25(OH)2D3. No changes in serum FGF-23 levels were observed in volunteers following ingestion of oral phosphate binders/low dietary phosphate intake, which led to a decline in phosphate excretion or during the subsequent repletion with inorganic phosphate through oral phosphate and a normal diet. Circulating FGF-23 was significantly elevated in patients with CKD and its concentration correlated with renal creatinine clearance. In healthy volunteers, FGF-23 levels did not change after phosphate deprivation or phosphate loading.

FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting.

FGF-23, a novel member of the FGF family, is the product of the gene mutated in autosomal dominant hypophosphatemic rickets (ADHR). FGF-23 has been proposed as a circulating factor causing renal phosphate wasting not only in ADHR (as a result of inadequate degradation), but also in tumor-induced osteomalacia (as a result of excess synthesis by tumor cells). Renal phosphate wasting occurs in approximately 50% of patients with McCune-Albright syndrome (MAS) and fibrous dysplasia of bone (FD), which result from postzygotic mutations of the GNAS1 gene. We found that FGF-23 is produced by normal and FD osteoprogenitors and bone-forming cells in vivo and in vitro. In situ hybridization analysis of FGF-23 mRNA expression identified "fibrous" cells, osteogenic cells, and cells associated with microvascular walls as specific cellular sources of FGF-23 in FD. Serum levels of FGF-23 were increased in FD/MAS patients compared with normal age-matched controls and significantly higher in FD/MAS patients with renal phosphate wasting compared with those without, and correlated with disease burden bone turnover markers commonly used to assess disease activity. Production of FGF-23 by FD tissue may play an important role in the renal phosphate-wasting syndrome associated with FD/MAS.

FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization.

There is evidence for a hormone/enzyme/extracellular matrix protein cascade involving fibroblastic growth factor 23 (FGF23), a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), and a matrix extracellular phosphoglycoprotein (MEPE) that regulates systemic phosphate homeostasis and mineralization. Genetic studies of autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH) identified the phosphaturic hormone FGF23 and the membrane metalloprotease PHEX, and investigations of tumor-induced osteomalacia (TIO) discovered the extracellular matrix protein MEPE. Similarities between ADHR, XLH, and TIO suggest a model to explain the common pathogenesis of renal phosphate wasting and defective mineralization in these disorders. In this model, increments in FGF23 and MEPE, respectively, cause renal phosphate wasting and intrinsic mineralization abnormalities. FGF23 elevations in ADHR are due to mutations of FGF23 that block its degradation, in XLH from indirect actions of inactivating mutations of PHEX to modify the expression and/or degradation of FGF23 and MEPE, and in TIO because of increased production of FGF23 and MEPE. Although this model is attractive, several aspects need to be validated. First, the enzymes responsible for metabolizing FGF23 and MEPE need to be established. Second, the physiologically relevant PHEX substrates and the mechanisms whereby PHEX controls FGF23 and MEPE metabolism need to be elucidated. Finally, additional studies are required to establish the molecular mechanisms of FGF23 and MEPE actions on kidney and bone, as well as to confirm the role of these and other potential "phosphatonins," such as frizzled related protein-4, in the pathogenesis of the renal and skeletal phenotypes in XLH and TIO. Unraveling the components of this hormone/enzyme/extracellular matrix pathway will not only lead to a better understanding of phosphate homeostasis and mineralization but may also improve the diagnosis and treatment of hypo- and hyperphosphatemic disorders.

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.

The Autosomal Dominant Hypophosphatemic Rickets R176Q Mutation in Fibroblast Growth Factor 23 Resists Proteolytic Cleavage and Enhances in Vivo Biological Potency

Missense mutations in fibroblast growth factor 23 (FGF23) are the cause of autosomal dominant hypophosphatemic rickets (ADHR). The mutations (R176Q, R179W, and R179Q) replace Arg residues within a subtilisin-like proprotein convertase (SPC) cleavage site (RXXR motif), leading to protease resistance of FGF23. The goals of this study were to examine in vivo the biological potency of the R176Q mutant FGF23 form and to characterize alterations in homeostatic mechanisms that give rise to the phenotypic presentation of this disorder. For this, wild type and R176Q mutant FGF23 were overexpressed in the intact animals using a tumor-bearing nude mouse system. At comparable circulating levels, the mutant form was more potent in inducing hypophosphatemia, in decreasing circulating concentrations of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), and in causing rickets and osteomalacia in these animals compared with wild type FGF23. Parameters of calcium homeostasis were also altered, leading to secondary hyperparathyroidism and parathyroid gland hyperplasia. However, the raised circulating levels of parathyroid hormone were ineffective in normalizing the reduced 1,25(OH)(2)D(3) levels by increasing renal expression of 25(OH)D(3)-1alpha-hydroxylase (Cyp40) to promote its synthesis and by decreasing that of 25(OH)D(3)-24-hydroxylase (Cyp24) to prevent its catabolism. The findings provide direct in vivo evidence that missense mutations from ADHR kindreds are gain-of-function mutations that retain and increase the protein's biological potency. Moreover, for the first time, they define a potential role for FGF23 in dissociating parathyroid hormone actions on mineral fluxes and on vitamin D metabolism at the level of the kidney.

Human Fibroblast Growth Factor-23 Mutants Suppress Na+-dependent Phosphate Co-transport Activity and 1α,25-Dihydroxyvitamin D3 Production

The human fibroblast growth factor 23 (hFGF23) and its autosomal dominant hypophosphatemic rickets (ADHR) mutant genes were incorporated into animals by naked DNA injection to investigate the action on phosphate homeostasis in vivo. The hFGF23 mutants (R176Q, R179Q, and R179W) markedly reduced serum phosphorus (6.2-6.9 mg/dl) compared with the plasmid MOCK (8.5 mg/dl). However, native hFGF23 did not affect serum phosphorus (8.6 mg/dl). Both hFGF23 and hFGF23R179Q mRNAs were expressed more than 100-fold in the liver 4 days after injection, however, the C-terminal portion of hFGF23 was detected only in the serum from hFGF23R179Q-injected animals (1109 pg/ml). hFGF23R179Q mutant was secreted as a 32-kDa protein, whereas, native hFGF23 was detected as a 20-kDa protein in the cell-conditioned media. These results suggest the hFGF23R179Q protein is resistant to intracellular proteolytic processing. The hFGF23R179Q suppressed Na/P(i) co-transport activities both in kidney and in small intestine by 45 and 30%, respectively, as well as serum 1alpha,25-dihydroxyvitamin D(3) to less than 15 pg/ml. However, it had little effect on serum parathyroid hormone (PTH). Infusion of hFGF23R179Q protein normalized serum phosphorus in thyroparathyroidectomized rats without affecting serum calcium. Taken together, the FGF23 mutants reduce both phosphate uptake in intestine and phosphate reabsorption in kidney, independent of PTH action.

New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia.

Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.

Mutant FGF-23 Responsible for Autosomal Dominant Hypophosphatemic Rickets Is Resistant to Proteolytic Cleavage and Causes Hypophosphatemia in Vivo

Mutant FGF-23 Responsible for Autosomal Dominant Hypophosphatemic Rickets Is Resistant to Proteolytic Cleavage and Causes Hypophosphatemia in Vivo

Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.

FGF-23 is involved in the pathogenesis of two similar hypophosphatemic diseases, autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced osteomalacia (TIO). We have shown that the overproduction of FGF-23 by tumors causes TIO. In contrast, ADHR derives from missense mutations in FGF-23 gene. However, it has been unclear how those mutations affect phosphate metabolism. Therefore, we produced mutant as well as wild-type FGF-23 proteins and examined their biological activity. Western blot analysis using site-specific antibodies showed that wild-type FGF-23 secreted into conditioned media was partially cleaved between Arg(179) and Ser(180). In addition, further processing of the cleaved N-terminal portion was observed. In constrast, mutant FGF-23 proteins found in ADHR were resistant to the cleavage. In order to clarify which molecule has the biological activity to induce hypophosphatemia, we separated full-length protein, the N-terminal and C-terminal fragments of wild-type FGF-23. When the activity of each fraction was examined in vivo, only the full-length FGF-23 decreased serum phosphate. Mutant FGF-23 protein that was resistant to the cleavage also retained the activity to induce hypophosphatemia. The extent of hypophosphatemia induced by the single administration of either wild-type or the mutant full-length FGF-23 protein was similar. In addition, implantation of CHO cells expressing the mutant FGF-23 protein caused hypophosphatemia and the decrease of bone mineral content. We conclude that ADHR is caused by hypophosphatemic action of mutant full-length FGF-23 proteins that are resistant to the cleavage between Arg(179) and Ser(180).

Novel phosphate-regulating genes in the pathogenesis of renal phosphate wasting disorders.

Over the past decade, three classes of Na/Pi cotransporters have been identified in mammalian kidney. The type IIa Na/Pi cotransporter, Npt2, is the most abundant and is expressed in the brush-border membrane of renal proximal tubular cells where the bulk of filtered inorganic phosphate (Pi) is reabsorbed. Disruption of the Npt2 gene in mice underscored the importance of Npt2 in the overall maintenance of Pi homeostasis and demonstrated that Npt2 is the target for regulation of proximal tubular Pi reabsorption by parathyroid hormone and dietary Pi. The regulation is post-transcriptional and largely occurs by brush-border membrane retrieval and insertion of Npt2 protein. Of great interest is the recent identification of novel Pi regulating genes, PHEX and FGF23, that play a role in the pathophysiology of inherited (X-linked hypophosphatemia and autosomal dominant hypophosphatemic rickets) and acquired (oncogenic hypophosphatemic rickets) disorders characterized by renal Pi wasting and associated skeletal abnormalities. Studies are currently underway to elucidate the molecular basis for impaired renal Pi reabsorption in these disorders and to determine the precise physiological role of PHEX and FGF-23 in the regulation of Pi homeostasis.

FGF-23 on hypophosphatemic rickets/osteomalacia

Recently, fibroblast growth factor 23 (FGF-23) has been identified as a causative factor of hypophosphatemic rickets, which was previously designated "phosphatonin". The pathogenesis of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and oncogenic osteomalacia (OOM) was discussed.

Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23

The gene for the renal phosphate wasting disorder autosomal-dominant hypophosphatemic rickets (ADHR) is FGF23, which encodes a secreted protein related to the fibroblast growth factors (FGFs). We previously detected missense mutations R176Q, R179W, and R179Q in FGF23 from ADHR kindreds. The mutations replace R residues within a subtilisin-like proprotein convertase (SPC) cleavage site 176RHTR-179 (RXXR motif). The goal of these studies was to determine if the ADHR mutations lead to protease resistance of FGF-23. The ADHR mutations were introduced into human FGF-23 cDNA clones with or without an N-terminal FLAG tag by site-directed mutagenesis and were transiently transfected into HEK293 cells. Protein expression was determined by Western analyses. Antibodies directed toward the C-terminal portion of FGF-23 revealed that the native FGF-23 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media; however, the three mutated proteins were detected only as the 32 kD band. An N-terminal FLAG-tagged native FGF-23 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody, whereas the R176Q mutant resolved primarily as the 36 kD protein species. Cleavage of FGF-23 was not enhanced by extracellular incubation of FGF-23 with HEK293 cells. Native and mutant FGF-23s bound heparin. FGF-23 proteins containing the ADHR mutations are secreted, and produce polypeptides less sensitive to protease cleavage than wild-type FGF-23. Therefore, the ADHR mutations may protect FGF-23 from proteolysis, thereby potentially elevating circulating concentrations of FGF-23 and leading to phosphate wasting in ADHR patients.

Hypophosphatemia and rickets/osteomalacia

It is important to know the pathophysiology of the inherited hypophosphatemic disorders for the research on the relationship between hypophosphatemia and rickets/osteomalacia. And the research on the pathogenesis of the X-linked hypophosphatemic vitamin D resistant rickets/osteomalacia has played central roles in this field. After the identification of PHEX gene for the responsible gene of the disorder, major interest of the research has shifted to the identification of phosphatonin, the natural substrate of PHEX and the novel phosphate-regulating hormone. Recent discovery of FGF23 for the responsible gene of oncogenic osteomalacia and autosomal dominant hypophosphatemic rickets may lead our knowledge on the phosphate regulation system to the new stage.

A case of neuroendocrine oncogenic osteomalacia associated with a PHEX and fibroblast growth factor-23 expressing sinusidal malignant schwannoma

Oncogenic osteomalacia is a rare paraneoplastic syndrome that is characterized biochemically by hypophosphatemia and low plasma 1,25-dihydroxyvitamin D 3, and clinically by osteomalacia, pseudofractures, bone pain, fatigue, and muscle weakness. We present a patient with a malignant schwannoma as the underlying cause of this disorder. A permanent cell line (HMS-97) derived from this tumor showed evidence of neuroendocrine differentiation by immunohistochemistry and of neurosecretory activity by electron microscopy. The cell line did express PHEX (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) and FGF-23 (fibroblast growth factor-23) transcripts on northern hybridization; however, none of the known mutations from the related mendelian disorders of X-linked hypophosphatemic rickets or autosomal-dominant hypophosphatemic rickets could be detected. Tumor cell (HMS-97)-derived conditioned medium did not inhibit phosphate transport in a standard opossum kidney cell assay and in animal experiments. The medium also showed no PTH1- or PTH2-receptor-stimulating bioactivity. HMS-97 cells might be useful for further studies that aim to determine the genetic mechanism that leads to the observed PHEX and FGF-23 expression, both of which might have a direct role in the pathogenesis of oncogenic osteomalacia. In addition, these cells might be a useful tool for the investigation of neuroendocrine Schwann cell function and autoimmune peripheral nerve disease.

FGF-23 Inhibits Renal Tubular Phosphate Transport and Is a PHEX Substrate

Oncogenic osteomalacia (OOM), X-linked hypophosphatemia (XLH), and autosomal dominant hypophosphatemic rickets (ADHR) are phenotypically similar disorders characterized by hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum calcitriol concentrations, normal serum concentrations of calcium and parathyroid hormone, and defective skeletal mineralization. XLH results from mutations in the PHEX gene, encoding a membrane-bound endopeptidase, whereas ADHR is associated with mutations of the gene encoding FGF-23. Recent evidence that FGF-23 is expressed in mesenchymal tumors associated with OOM suggests that FGF-23 is responsible for the phosphaturic activity previously termed “phosphatonin.” Here we show that both wild-type FGF-23 and the ADHR mutant, FGF-23(R179Q), inhibit phosphate uptake in renal epithelial cells. We further show that the endopeptidase, PHEX, degrades native FGF-23 but not the mutant form. Our results suggest that FGF-23 is involved in the pathogenesis of these three hypophosphatemic disorders and directly link PHEX and FGF-23 within the same biochemical pathway.

FGF23, hypophosphatemia, and rickets: Has phosphatonin been found?

The mineralization of cartilage and bone matrix requires adequate supplies of calcium and phosphate. Among the causes of defective mineralization of bone (osteomalacia) and defective mineralization of cartilage (rickets) are renal phosphate-wasting disorders that produce hypophosphatemia. Phosphate wasting is either inherited as X-linked hypophosphatemic rickets or autosomal dominant hypophosphatemic rickets, or acquired, as can occur in patients with a variety of benign mesenchymal tumors (hemangiopericytomas, fibromas, angiosarcomas, etc.) (1). Osteomalacia induced by tumors is invariably curable if the tumor can be found and resected, indicating that it has a humoral basis. A paper by Shimada et al. (2) in this issue of PNAS identifies a member of the fibroblast growth factor family, FGF23, as the humoral factor that is secreted by tumors to cause tumor-induced osteomalacia. With the discovery that a protease mutation and a cleavage site mutation may cause the same disease, the puzzle pieces could fit together nicely.

FGF23, hypophosphatemia, and rickets: has phosphatonin been found?

The mineralization of cartilage and bone matrix requires adequate supplies of calcium and phosphate. Among the causes of defective mineralization of bone (osteomalacia) and defective mineralization of cartilage (rickets) are renal phosphate-wasting disorders that produce hypophosphatemia. Phosphate wasting is either inherited as X-linked hypophosphatemic rickets or autosomal dominant hypophosphatemic rickets, or acquired, as can occur in patients with a variety of benign mesenchymal tumors (hemangiopericytomas, fibromas, angiosarcomas, etc.) (1). Osteomalacia induced by tumors is invariably curable if the tumor can be found and resected, indicating that it has a humoral basis. A paper by Shimada et al. (2) in this issue of PNAS identifies a member of the fibroblast growth factor family, FGF23, as the humoral factor that is secreted by tumors to cause tumor-induced osteomalacia. With the discovery that a protease mutation and a cleavage site mutation may cause the same disease, the puzzle pieces could fit together nicely.