calcitriol and Hypophosphatemia

Phosphate homeostasis involves several major organs that are the skeleton, the intestine, the kidney, and parathyroid glands. Major regulators of phosphate homeostasis are parathormone, fibroblast growth factor 23, 1,25-dihydroxyvitamin D, which respond to variations of serum phosphate levels and act to increase or decrease intestinal absorption and renal tubular reabsorption, through the modulation of expression of transcellular transporters at the intestinal and/or renal tubular level. Any acquired or genetic dysfunction in these major organs or regulators may induce hypo- or hyperphosphatemia. The causes of hypo- and hyperphosphatemia are numerous. This review develops the main causes of acquired and genetic hypo- and hyperphosphatemia.

Topics: Fibroblast Growth Factors; Homeostasis; Humans; Hyperphosphatemia; Hypophosphatemia; Intestines; Kidney; Parathyroid Hormone; Phosphates; Vitamin D

Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.

Topics: Animals; Biomarkers; Bone and Bones; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Homeostasis; Humans; Hyperphosphatemia; Hypophosphatemia; Intestinal Absorption; Parathyroid Hormone; Phosphates; Renal Reabsorption; Vitamin D

Serum phosphate is maintained within a certain range by intestinal phosphate absorption, renal phosphate handling, and dynamic equilibrium with the intracellular phosphate or phosphate in bone. Of these, renal phosphate handling is believed to be the main determinant of the serum phosphate level at least in a chronic state. Most of the phosphate filtered from the glomeruli is reabsorbed in proximal tubules through type 2a and 2c sodium-phosphate co-transporters. Therefore, chronic hypophosphatemia and hyperphosphatemia are usually caused by changes in renal phosphate handling. Several humoral factors, including parathyroid hormone and insulin-like growth factor-I, have been known to affect proximal tubular phosphate reabsorption. In addition, fibroblast growth factor 23 (FGF23) was shown to inhibit phosphate reabsorption by suppressing the expression of type 2a and 2c sodium-phosphate co-transporters. FGF23 also reduces the circulatory 1,25-dihydroxyvitamin D [1,25 (OH)2D] level. FGF23 is produced by bone, especially by osteocytes, and works in the kidney by binding to the Klotho-FGF receptor complex. It has been shown that excess actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia with impaired proximal tubular phosphate reabsorption and a rather low 1,25 (OH)2D level. In contrast, deficient actions of FGF23 result in familial hyperphosphatemic tumoral calcinosis with enhanced proximal tubular phosphate reabsorption and high 1,25 (OH)2D. These results indicate that FGF23 is a hormone regulating phosphate and vitamin D metabolism. In addition, several hypophosphatemic and hyperphosphatemic diseases can be classified as endocrine diseases caused by the aberrant actions of FGF23. It is possible that some drugs that modulate the action of FGF23 can be novel therapeutic measures for abnormal phosphate metabolism in the future.

Topics: Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperphosphatemia; Hypophosphatemia; Kidney; Osteomalacia; Phosphates; Phosphorus Metabolism Disorders; Rickets; Vitamin D

To describe emerging understanding of fibroblast growth factor 23 (FGF23) - a bone-derived hormone that inhibits phosphate reabsorption and calcitriol production by kidney and participates as the principle phosphaturic factor in a bone-kidney axis coordinating systemic phosphate homeostasis and bone mineralization.. FGF23 (a circulating factor made by osteocytes in bone) inhibits phosphate reabsorption and 1,25(OH)2D production by kidney. Physiologically, FGF23 is a counter-regulatory phosphaturic hormone for vitamin D and coordinates systemic phosphate homeostasis with skeletal mineralization. Pathologically, high circulating FGF23 levels cause hypophosphatemia, decreased 1,25(OH)2D production, elevated parathyroid hormone and rickets/osteomalacia. FGF23 mutations impairing its degradation cause autosomal dominant hypophosphatemic rickets. Respective loss-of-function mutations of osteocyte gene products DMP1 and Phex cause autosomal recessive hypophosphatemic rickets and X-linked hypophosphatemic rickets, initiating increased FGF23 production. Low FGF23 levels lead to hyperphosphatemia, elevated 1,25(OH)2D, and soft-tissue calcifications. FGF23 is markedly increased in chronic renal disease, but its role remains undefined.. FGF23 discovery has uncovered primary regulatory pathways and new systems biology governing bone mineralization, vitamin D metabolism, parathyroid gland function, and renal phosphate handling. FGF23 assessment will become important in diagnosing hypophosphatemic and hyperphosphatemic disorders, for which pharmacological regulation of FGF23 levels may provide novel treatments.

Topics: Animals; Bone and Bones; Calcification, Physiologic; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glycoproteins; Homeostasis; Humans; Hypophosphatemia; Kidney; Mice; Parathyroid Hormone; Phosphates; Phosphoproteins; Receptors, Fibroblast Growth Factor; Vitamin D

Topics: Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibrous Dysplasia, Polyostotic; Humans; Hyperparathyroidism; Hypoparathyroidism; Hypophosphatemia; Parathyroid Hormone; Parathyroid Hormone-Related Protein; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphorus; Thyrotoxicosis; Vitamin D

Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation.. Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23.. Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk.. Plasma phosphate fell from 3.4 +/- 0.6 mg/dl at baseline to 1.8 +/- 0.6 mg/dl at wk 1 (P < 0.0001) associated with a fall in percentage tubular reabsorption of phosphate (90 +/- 4.8 to 68 +/- 13; P < 0.001) and 1,25(OH)(2)D (54 +/- 25 to 9 +/- 8 pg/ml; P < 0.001). These indices remained significantly suppressed at wk 2 and 3. 25(OH)D levels were unchanged. FGF23 increased significantly from 43.5 pg/ml at baseline to 177 pg/ml at wk 1 (P < 0.001) with levels correlating with both serum phosphate (R = -0.74; P <0.05) and 1,25(OH)(2)D (R = -0.71; P < 0.05).. Parenteral iron suppresses renal tubular phosphate reabsorption and 1alpha-hydroxylation of vitamin D resulting in hypophosphatemia. Our data suggest that this is mediated by an increase in FGF23.

Topics: Adult; Aged; Aged, 80 and over; Female; Ferric Compounds; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hydroxylation; Hypophosphatemia; Injections, Intravenous; Iron; Middle Aged; Parathyroid Hormone; Phosphates; Up-Regulation; Vitamin D; Young Adult

Both FGF-23 and PTH inhibit renal phosphate reabsorption. We treated two patients with TIO and FGF-23-mediated hypophosphatemia with cinacalcet to test the hypothesis that medicinally induced hypoparathyroidism would decrease renal phosphate wasting. Cinacalcet treatment resulted in increased renal phosphate reabsorption, allowed for a decrease in phosphate supplementation, and showed evidence of bone healing in one of the two patients.. Tumor-induced osteomalacia (TIO) is a rare, acquired disease of renal phosphate wasting, which results in hypophosphatemia and osteomalacia. It is caused by mesenchymal tumors that produce the phosphate and vitamin D-regulating hormone, fibroblast growth factor (FGF)-23. Removal of the tumor is curative, but the tumors are often difficult to locate. Medical treatment involves high doses of oral phosphate and calcitriol, but the phosphate is often poorly tolerated and leads to diarrhea. Because PTH also promotes phosphaturia, and patients with hypoparathyroidism are hyperphosphatemic in the setting of elevated serum FGF-23, we postulated that the calcium-sensing receptor agonist, cinacalcet, which can induce hypoparathyroidism, would be an effective adjuvant in the treatment of TIO.. Two subjects with presumed TIO in whom the tumor was not located after extensive testing and who did not tolerate medical therapy with phosphorus and calcitriol were treated with cinacalcet.. Neither treatment with phosphorus nor combined treatment with phosphorus and calcitriol had an effect on serum FGF-23 levels. Treatment with cinacalcet resulted in increased renal phosphate reabsorption and serum phosphorus and allowed for a decrease in phosphate supplementation to a dose that was tolerated. On this regimen, one patient showed significant bone healing as shown by resolution of activity on bone scan and lack of osteomalacia as assessed by histomorphometry.. These data show that medically induced hypoparathyroidism with cinacalcet is a therapeutic option for disorders of FGF-23-mediated hypophosphatemia and that, in the absence of PTH, the phosphaturic effect of FGF-23 is decreased.

Topics: Bone and Bones; Calcitriol; Calcium; Cinacalcet; Drug Therapy, Combination; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hydrochlorothiazide; Hypoparathyroidism; Hypophosphatemia; Kidney; Male; Middle Aged; Naphthalenes; Neoplasms; Osteomalacia; Parathyroid Hormone; Phosphates; Phosphorus; Treatment Outcome; Vitamin D

Phosphate homeostasis is critical for many cellular processes and is tightly regulated. The sodium-dependent phosphate cotransporter, NaPi2a, is the major regulator of urinary phosphate reabsorption in the renal proximal tubule. Its activity is dependent upon its brush border localization that is regulated by fibroblast growth factor 23 (FGF23) and PTH. High levels of FGF23, as are seen in the Hyp mouse model of human X-linked hypophosphatemia, lead to renal phosphate wasting. Long-term treatment of Hyp mice with 1,25-dihydroxyvitamin D (1,25D) or 1,25D analogues has been shown to improve renal phosphate wasting in the setting of increased FGF23 mRNA expression. Studies were undertaken to define the cellular and molecular basis for this apparent FGF23 resistance. 1,25D increased FGF23 protein levels in the cortical bone and circulation of Hyp mice but did not impair FGF23 cleavage. 1,25D attenuated urinary phosphate wasting as early as one hour postadministration, without suppressing FGF23 receptor/coreceptor expression. Although 1,25D treatment induced expression of early growth response 1, an early FGF23 responsive gene required for its phosphaturic effects, it paradoxically enhanced renal phosphate reabsorption and NaPi2a protein expression in renal brush border membranes (BBMs) within one hour. The Na-H+ exchange regulatory factor 1 (NHERF1) is a scaffolding protein thought to anchor NaPi2a to the BBM. Although 1,25D did not alter NHERF1 protein levels acutely, it enhanced NHERF1-NaPi2a interactions in Hyp mice. 1,25D also prevented the decrease in NHERF1/NaPi2a interactions in PTH-treated wild-type mice. Thus, these investigations identify a novel role for 1,25D in the hormonal regulation of renal phosphate handling.

Topics: Animals; Cell Line; Epithelial Cells; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; Hypophosphatemia; Hypophosphatemia, Familial; Kidney Tubules, Proximal; Male; MAP Kinase Signaling System; Mice; Protein Transport; Receptors, Fibroblast Growth Factor; Sodium-Phosphate Cotransporter Proteins, Type IIa; Vitamin D

Topics: Adult; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Foot Diseases; Humans; Hypophosphatemia; Male; Neoplasm Proteins; Neoplasms, Connective Tissue; Osteomalacia; Paraneoplastic Syndromes; Skin Neoplasms; Toes; Vitamin D

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that acts on the proximal tubule to decrease phosphate reabsorption and serum levels of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂ Vitamin D₃]. Abnormal FGF23 metabolism has been implicated in several debilitating hypophosphatemic and hyperphosphatemic disorders. The renal receptors responsible for the phosphaturic actions of FGF23 have not been elucidated. There are four fibroblast growth factor receptors (FGFR); 1-4 with "b" and "c" isoforms for receptors 1, 2, and 3. FGFR1, 3, and 4 are expressed in the mouse proximal tubule, and deletion of any one receptor did not affect serum phosphate levels, suggesting that more than one receptor is involved in mediating the phosphaturic actions of FGF23. To determine the receptors responsible for the phosphaturic actions of FGF23, we studied Fgfr1 (kidney conditional) and Fgfr4 (global) double mutant mice (Fgfr1⁻/⁻/Fgfr4⁻/⁻). Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have higher FGF23 levels than their wild-type counterparts (108.1 ± 7.3 vs. 4,953.6 ± 675.0 pg/ml; P < 0.001). Despite the elevated FGF23 levels, Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have elevated serum phosphorus levels, increased brush-border membrane vesicle (BBMV) phosphate transport, and increased Na-P(i) cotransporter 2c (NaPi-2c) protein expression compared with wild-type mice. These data are consistent with FGFR1 and FGFR4 being the critical receptors for the phosphaturic actions of FGF23.

Topics: Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Hyperphosphatemia; Hypophosphatemia; Kidney Tubules, Proximal; Klotho Proteins; MAP Kinase Signaling System; Mice; Microvilli; Parathyroid Hormone; Phosphates; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 3; Receptor, Fibroblast Growth Factor, Type 4; RNA, Messenger; Sodium-Phosphate Cotransporter Proteins, Type IIa; Vitamin D

Topics: Bone and Bones; Calcium; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Kidney Diseases; Parathyroid Hormone; Phosphates; Vitamin D

The X-linked hypophosphatemic (Hyp) mouse carries a loss-of-function mutation in the phex gene and is characterized by hypophosphatemia due to renal phosphate (Pi) wasting, inappropriately suppressed 1,25-dihydroxyvitamin D [1,25(OH)₂D] production, and rachitic bone disease. Increased serum fibroblast growth factor-23 concentration is responsible for the disordered metabolism of Pi and 1,25(OH)₂D. In the present study, we tested the hypothesis that chronic inhibition of fibroblast growth factor-23-induced activation of MAPK signaling in Hyp mice can reverse their metabolic derangements and rachitic bone disease. Hyp mice were administered the MAPK inhibitor, PD0325901 orally for 4 wk. PD0325901 induced a 15-fold and 2-fold increase in renal 1α-hydroxylase mRNA and protein abundance, respectively, and thereby higher serum 1,25(OH)₂D concentrations (115 ± 13 vs. 70 ± 16 pg/ml, P < 0.05), compared with values in vehicle-treated Hyp mice. With PD0325901, serum Pi levels were higher (5.1 ± 0.5 vs. 3 ± 0.2 mg/dl, P < 0.05), and the protein abundance of sodium-dependent phosphate cotransporter Npt2a, was greater than in vehicle-treated mice. The rachitic bone disease in Hyp mice is characterized by abundant unmineralized osteoid bone volume, widened epiphyses, and disorganized growth plates. In PD0325901-treated Hyp mice, mineralization of cortical and trabecular bone increased significantly, accompanied by a decrease in unmineralized osteoid volume and thickness, as determined by histomorphometric analysis. The improvement in mineralization in PD0325901-treated Hyp mice was confirmed by microcomputed tomography analysis, which showed an increase in cortical bone volume and thickness. These findings provide evidence that in Hyp mice, chronic MAPK inhibition improves disordered Pi and 1,25(OH)₂D metabolism and bone mineralization.

Topics: Animals; Benzamides; Bone and Bones; Bone Diseases; Diphenylamine; Disease Models, Animal; Enzyme Inhibitors; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Hypophosphatemia; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Minerals; Mitogen-Activated Protein Kinase Kinases; Mutation; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphates; Signal Transduction; Vitamin D

Persistence of inappropriately high serum levels of fibroblast growth factor-23 (FGF23), a recently discovered phosphaturic hormone, has been reported to play an important role in the pathogenesis of posttransplant hypophosphatemia. The aim of the present study was to evaluate FGF23 in the early posttransplant period and study the complex associations between FGF23, parathyroid hormone (PTH), 1,25(OH)(2) vitamin D, and phosphate in transplant patients.. We performed a cross-sectional observational study of 42 adult kidney recipients in the early posttransplant period (<6 months). Fasting serum samples and 24-hour urine samples were collected during a routine follow-up outpatient visit. Serum creatinine, calcium, phosphate, magnesium and urinary creatinine, calcium, magnesium, and phosphate were measured using standard assays. We also studied concentrations of 25 hydroxyvitamin D, 1,25(OH)(2) vitamin D, intact PTH, and circulating FGF23.. Median values for the different parameters studied were as follows: 9.9 ± 0.6 mg/dL, phosphatemia 3.3 ± 0.7 mg/dL, estimated glomerular filtration rate (eGFR; 41.1 ± 14.0 mL/min, phosphate reabsorption rate 68.4% ± 10.7%, PTH 94.5 ng/L (53.8-199.5), calcitriol 33.0 pg/mL (24.0-44.1), calcidiol 27.3 ng/mL (17.0-38.0), FGF23 139 pg/mL (88-221), and calciuria 62.5 mg/d (40.3-101.3). The variables significantly associated with serum FGF23 levels were phosphate reabsorption rate (r = .493; P = .001), calcitriol (r = .399; P = .009), eGFR (r = .557; P < .001), PTH (0.349; P = .024).. Elevated serum levels of FGF23 could explain the deficiency of calcitriol and elevated renal phosphorus wasting in the early posttransplant period. All treatments that can lead to increased serum phosphate levels (eg, oral medication or calcitriol) should be carefully evaluated, since increased phosphatemia could further stimulate secretion of FGF23 and prolong high phosphorus loss.

Topics: Biomarkers; Calcium; Chi-Square Distribution; Cross-Sectional Studies; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Humans; Hypophosphatemia; Kidney Transplantation; Parathyroid Hormone; Phosphorus; Time Factors; Up-Regulation; Vitamin D

In autosomal dominant hypophosphatemic rickets (ADHR), fibroblast growth factor 23 (FGF23) resists cleavage, causing increased plasma FGF23 levels. The clinical phenotype includes variable onset during childhood or adulthood and waxing/waning of hypophosphatemia. Delayed onset after puberty in females suggests iron status may be important.. Studies were performed to test the hypothesis that plasma C-terminal and intact FGF23 concentrations are related to serum iron concentrations in ADHR.. Cross-sectional and longitudinal studies of ADHR and a cross-sectional study in healthy subjects were conducted at an academic medical center.. Participants included 37 subjects with ADHR mutations from four kindreds and 158 healthy adult controls.. The relationships of serum iron concentrations with plasma C-terminal and intact FGF23 concentrations were evaluated.. Serum phosphate and 1,25-dihydroxyvitamin D correlated negatively with C-terminal FGF23 and intact FGF23 in ADHR but not in controls. Serum iron was negatively correlated to both C-terminal FGF23 (r = -0.386; P < 0.05) and intact FGF23 (r = -0.602; P < 0.0001) in ADHR. However, control subjects also demonstrated a negative relationship of serum iron with C-terminal FGF23 (r = -0.276; P < 0.001) but no relationship with intact FGF23. Longitudinally in ADHR subjects, C-terminal FGF23 and intact FGF23 concentrations changed negatively with iron concentrations (P < 0.001 and P = 0.055, respectively), serum phosphate changed negatively with C-terminal FGF23 and intact FGF23 (P < 0.001), and there was a positive relationship between serum iron and phosphate (P < 0.001).. Low serum iron is associated with elevated FGF23 in ADHR. However, in controls, low serum iron was also associated with elevated C-terminal FGF23, but not intact FGF23, suggesting cleavage maintains homeostasis despite increased FGF23 expression.

Topics: Adult; Cross-Sectional Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Iron; Male; Middle Aged; Mutation; Rickets; Vitamin D

Rickets is a growth plate abnormality observed in growing animals and humans. Rachitic expansion of the hypertrophic chondrocyte layer of the growth plate, in the setting of hypophosphatemia, is due to impaired apoptosis of these cells. Rickets is observed in humans and mice with X-linked hypophosphatemia that is associated with renal phosphate wasting secondary to elevated levels of fibroblast growth factor-23. Rickets is also seen in settings of impaired vitamin D action, due to elevated PTH levels that increase renal phosphate excretion. However, mice with hypophosphatemia secondary to ablation of the renal sodium-dependent phosphate transport protein 2a (Npt2a), have not been reported to develop rickets. Because activation of the mitochondrial apoptotic pathway by phosphate is required for hypertrophic chondrocyte apoptosis in vivo, investigations were undertaken to address this paradox. Analyses of the Npt2a null growth plate demonstrate expansion of the hypertrophic chondrocyte layer at 2 wk of age, with resolution of this abnormality by 5 wk of age. This is temporally associated with an increase in circulating levels of 1,25-dihydroxyvitamin D. To address whether the receptor-dependent actions of this steroid hormone are required for normalization of the growth plate phenotype, the Npt2a null mice were mated with mice lacking the vitamin D receptor or were rendered vitamin D deficient. These studies demonstrate that the receptor-dependent actions of 1,25-dihydroxyvitamin D are required for maintenance of a normal growth plate phenotype in the Npt2a null mice.

Topics: Animals; Calcium; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Growth Plate; Hypophosphatemia; Mice; Mice, Inbred C57BL; Mice, Knockout; Parathyroid Hormone; Phosphates; Receptors, Calcitriol; Rickets; Sodium-Phosphate Cotransporter Proteins, Type IIa; Vitamin D

Hyp mice possess a mutation that inactivates the phosphate-regulating gene, which is homologous to the endopeptidases of the X-chromosome (PHEX). The mutation is associated with severe hypophosphatemia due to excessive urinary phosphate wasting. Such urinary phosphate wasting in Hyp mice is associated with an increased serum accumulation of fibroblast growth factor (FGF) 23. We wanted to determine the biological significance of increased serum FGF23 levels and concomitant hypophosphatemia in Hyp mice and to evaluate whether FGF23 activity could be modified by manipulating klotho (a cofactor of FGF23 signaling). We generated Hyp and klotho double-mutant mice (Hyp/klotho(-/-)). Severe hypophosphatemia of Hyp mice was reversed to hyperphosphatemia in Hyp/klotho(-/-) double mutants, despite the fact that the double mutants showed significantly increased serum levels of FGF23. Hyperphosphatemia in Hyp/klotho(-/-) mice was associated with increased renal expression of sodium/phosphate cotransporter 2a (NaPi2a) protein. Exogenous injection of bioactive parathyroid hormone 1-34 down-regulated renal expression of NaPi2a and consequently reduced serum levels of phosphate in Hyp/klotho(-/-) mice. Moreover, in contrast to the Hyp mice, the Hyp/klotho(-/-) mice showed significantly higher serum levels of 1,25-dihydroxyvitamin D and developed extensive calcification in soft tissues and vascular walls. Furthermore, compared with the Hyp mice, Hyp/klotho(-/-) mice were smaller in size, showed features of generalized tissue atrophy, and generally died by 15-20 wk of age. Our in vivo studies provide genetic evidence for a pathological role of increased FGF23 activities in regulating abnormal phosphate homeostasis in Hyp mice. Moreover, these results suggest that even when serum levels of FGF23 are significantly high, in the absence of klotho, FGF23 is unable to regulate systemic phosphate homeostasis. Our in vivo observations have significant clinical implications in diseases associated with increased FGF23 activity and suggest that the functions of FGF23 can be therapeutically modulated by manipulating the effects of klotho.

Topics: Animals; Calcium; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Hypophosphatemia; Klotho Proteins; Mice; Mice, Knockout; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphates; Sodium-Phosphate Cotransporter Proteins, Type IIa; Vitamin D

Klotho-knockout mice (klotho(-/-)) have increased renal expression of sodium/phosphate cotransporters (NaPi2a), associated with severe hyperphosphatemia. Such serum biochemical changes in klotho(-/-) mice lead to extensive soft-tissue anomalies and vascular calcification. To determine the significance of increased renal expression of the NaPi2a protein and concomitant hyperphosphatemia and vascular calcification in klotho(-/-) mice, we generated klotho and NaPi2a double-knockout (klotho(-/-)/NaPi2a(-/-)) mice.. Genetic inactivation of NaPi2a activity from klotho(-/-) mice reversed the severe hyperphosphatemia to mild hypophosphatemia or normophosphatemia. Importantly, despite significantly higher serum calcium and 1,25-dihydroxyvitamin D levels in klotho(-/-)/NaPi2a(-/-) mice, the vascular and soft-tissue calcifications were reduced. Extensive soft-tissue anomalies and cardiovascular calcification were consistently noted in klotho(-/-) mice by 6 weeks of age; however, these vascular and soft-tissue abnormalities were absent even in 12-week-old double-knockout mice. Klotho(-/-)/NaPi2a(-/-) mice also regained body weight and did not develop the generalized tissue atrophy often noted in klotho(-/-) single-knockout mice.. Our in vivo genetic manipulation studies have provided compelling evidence for a pathological role of increased NaPi2a activities in regulating abnormal mineral ion metabolism and soft-tissue anomalies in klotho(-/-) mice. Notably, our results suggest that serum phosphate levels are the important in vivo determinant of calcification and that lowering serum phosphate levels can reduce or eliminate soft-tissue and vascular calcification, even in presence of extremely high serum calcium and 1,25-dihydroxyvitamin D levels. These in vivo observations have significant clinical importance and therapeutic implications for patients with chronic kidney disease with cardiovascular calcification.

Topics: Animals; Blood Vessels; Bone and Bones; Calcinosis; Calcium; Female; Glucuronidase; Humans; Hypophosphatemia; Klotho Proteins; Male; Mice; Mice, Knockout; Phosphates; Sodium-Phosphate Cotransporter Proteins, Type IIa; Vitamin D

Fibroblast growth factor 23 (FGF23) is a phosphaturic factor that suppresses both sodium-dependent phosphate transport and production of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] in the proximal tubule. In vitro studies suggest that FGFR3 is the physiologically relevant receptor for FGF23 in the kidney, but this has not been established in vivo. Here, immunohistochemical analysis of the mouse kidney revealed that the proximal tubule expresses FGF receptor 3 (FGFR3) but not FGFR1, FGFR2, or FGFR4. Compared with wild-type mice, Hyp mice, which have elevated circulating levels of FGF23, exhibited low levels of serum phosphate and 1,25(OH)(2)D, reduced expression of the sodium-dependent phosphate transporter NPT2a in the proximal tubules, and low bone mineral density as a result of osteomalacia. In contrast, neither the serum phosphate nor 1,25(OH)(2)D levels were altered in FGFR3-null mice. For examination of the role of FGFR3 in mediating the effects of FGF23, Hyp mice were crossed with FGFR3-null mice; interestingly, this failed to correct the aforementioned metabolic abnormalities of Hyp mice. Ablation of FGFR4 also failed to correct hypophosphatemia in Hyp mice. Because the ablation of neither FGFR3 nor FGFR4 inhibited the renal effects of excess FGF23, the kidney localization of FGFR1 was investigated. FGFR1 co-localized with Klotho, the co-factor required for FGF23-dependent FGFR activation, in the distal tubule. In summary, neither FGFR3 nor FGFR4 is the principal mediator of FGF23 effects in the proximal tubule, and co-localization of FGFR1 and Klotho suggests that the distal tubule may be an effector site of FGF23.

Topics: Animals; Bone Density; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; Glucuronidase; Hypophosphatemia; Kidney Tubules; Klotho Proteins; Male; Mice; Models, Biological; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 3; Receptor, Fibroblast Growth Factor, Type 4; Vitamin D

Oncogenic osteomalacia (OOM) is characterised by tumour production of fibroblast growth factor 23 (FGF23) that results in hypophosphataemia and renal phosphate wasting, reduced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesis and osteomalacia. Here, we demonstrate the roles of serum FGF23 and 1,25(OH)2D3, together with the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), as biomarkers for OOM. A previously well 52-year-old man presented with a 2-year history of generalised musculoskeletal pain and proximal myopathy. He had hypophosphataemia, elevated serum alkaline phosphatase activity, low serum 1,25(OH)2D3 and a reduced tubular maximum of phosphate/glomerular filtration rate. These findings indicated a diagnosis of OOM, but magnetic resonance imaging (MRI) and octreotide scintigraphy did not identify any tumours. Treatment with oral phosphate and calcitriol resolved the symptoms and biochemical abnormalities within 6 months. Four years later, he relapsed whilst on treatment with oral phosphate and calcitriol. Serum FGF23 concentration was elevated and MRI identified a 2 cm tumour within Hoffa's fat pad of the left knee. Removal of the tumour resulted in a complete resolution of symptoms and normalisation of the serum biochemical abnormalities including serum FGF23. Histology demonstrated a phosphaturic mesenchymal tumour, mixed connective tissue variant (PMTMCT), which revealed immunostaining with anti-LYVE-1 antibody and hence the presence of lymphatic vessels. Serum FGF23 and 1,25(OH)2D3 were found to be reliable biomarkers for OOM. In addition, the demonstration of lymphatics in the PMTMCT helps to distinguish this tumour from most typical benign haemangiomas.

Topics: Administration, Oral; Alkaline Phosphatase; Biomarkers; Biomarkers, Tumor; Bone Neoplasms; Calcitriol; Chondrosarcoma, Mesenchymal; Endothelium, Vascular; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyaluronan Receptors; Hypophosphatemia; Knee; Lymphatic Vessels; Male; Middle Aged; Osteomalacia; Paraneoplastic Syndromes; Phosphates; Predictive Value of Tests; Vitamin D

Topics: Adenocarcinoma; Aged, 80 and over; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Male; Osteomalacia; Parathyroid Hormone; Prostatic Neoplasms; Syndrome; Vitamin D

Rickets is seen in association with vitamin D deficiency and in several genetic disorders associated with abnormal mineral ion homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansion of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observation that normalization of mineral ion homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR action. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additional models were examined: diet-induced hypophosphatemia/hypercalcemia and hypophosphatemia secondary to mutations in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturation and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activation of the caspase-9-mediated mitochondrial pathway.

Topics: Animals; Apoptosis; Blotting, Western; Calcium; Caspase 9; Caspases; Chondrocytes; Hypophosphatemia; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mutation; Parathyroid Hormone; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphates; Proteins; Rickets; Vitamin D

We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism.. The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes.. To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals.. An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h.. FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.

Topics: Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Homeostasis; Hypophosphatemia; Male; Mice; Phosphates; Rats; Recombinant Proteins; Time Factors; Vitamin D

To analyze the pathophysiology of hypophosphatemia in calcium nephrolithiasis, we investigated the relation between serum phosphorus, 1,25-dihydroxyvitamin D, and parathyroid hormone (PTH) levels in 63 consecutive patients with calcium nephrolithiasis, comparing them with 26 age-matched control subjects.. Serum phosphorus concentrations in normocalciuric and absorptive hypercalciuric stone formers were significantly decreased compared with control subjects (P<0.001 and P<0.01, respectively). The fractional excretion (TRP) and renal threshold (TmP/GFR) of phosphorus were significantly decreased in the subjects with nephrolithiasis (P<0.01 and P<0.001, respectively). Serum phosphorus concentrations were inversely correlated with serum 1, 25-dihydroxyvitamin D in control subjects and in absorptive hypercalciuric stone formers (P<0.01 and P <0.05, respectively), suggesting that the physiologic relation between phosphorus and 1, 25-dihydroxyvitamin D is maintained in these patients. Serum phosphorus concentrations in absorptive hypercalciuric patients, although related to 1,25-dihydroxyvitamin D, were not related to PTH even though PTH and 1,25-dihydroxyvitamin D concentrations were directly related (P<0.05). The lack of a relation between PTH and serum phosphorus concentrations in absorptive hypercalciuric stone formers was similar to that in controls. In normocalciuric stone formers, there was no relation between serum 1,25-dihydroxyvitamin D and serum phosphorus, but PTH and 1,25-dihydroxyvitamin D were inversely correlated (P<0.05).. Abnormal renal tubular function with a depressed rate of renal phosphorus transport and an abnormal 1,25-dihydroxyvitamin D concentration is common in nephrolithiasis. Differences in the relations between phosphorus and 1,25-dihydroxyvitamin D observed in hypercalciuric v normocalciuric subjects suggest that the pathogenesis of proximal tubulopathy differs among patients with nephrolithiasis.

Topics: Adult; Aged; Calcium; Case-Control Studies; Female; Humans; Hypophosphatemia; Kidney Calculi; Male; Middle Aged; Models, Biological; Parathyroid Hormone; Phosphorus; Vitamin D

X-linked hypophosphatemia is a metabolic bone disease occurring in both humans and mice. In mice, two different mutations (Hyp and Gy), occurring at separate but closely linked loci, have been proposed as models for this disease. Varying reports of the Vitamin D status of these two mutants has led us to reexamine the influence of diet on circulating calcitrophic hormones and mineral metabolism in both mutants. Hyp and Gy mice were raised on the B6C3H background, and both normal females and heterozygous mutant females were studied at 10 weeks of age. Animals were fed one of three diets at random: high (1.5% Ca and 1.0% P); medium (0.6% Ca and 0.6% P); or low (0.0% Ca and 0.6% P). After 3 days, serum and urine samples were collected. In comparison to mutant mice fed the high diet, both Hyp and Gy mice fed the low diet had decreased serum calcium levels, and further elevations in both serum alkaline phosphatase and serum parathyroid hormone (PTH). Serum 1,25-dihydroxyvitamin D levels were elevated by both the medium and low diets in all groups of mice over values obtained with the high diet. Mutant mice were significantly higher in serum PTH on all diets compared to normal mice fed the same diet. Mutant mice were not elevated in serum 1,25-dihydroxyvitamin D over normal mice when fed the high diet. However, both Hyp and Gy mice fed the medium and low diets were elevated in serum 1,25-dihydroxyvitamin D over normal mice. Serum PTH levels were correlated to serum 1,25-dihydroxyvitamin D levels with Hyp and Gy mice lying on the same line (r = 0.86; p < 0.0001). In summary, when Hyp and Gy mice are studied on the same genetic background and fed the same diet, similar responses are seen in PTH levels and 1,25-dihydroxyvitamin D levels. Both mutants should be useful in elucidating the pathophysiology of this poorly understood human disease.

Topics: Alkaline Phosphatase; Analysis of Variance; Animals; Bone Diseases, Metabolic; Calcium; Calcium, Dietary; Diet; Female; Genetic Linkage; Hypophosphatemia; Mice; Mice, Mutant Strains; Parathyroid Hormone; Phosphates; Random Allocation; Vitamin D; X Chromosome

A case of tumor-induced phosphaturic osteomalacia in a 54 year old man is reported. The patient was admitted because of progressive muscle spasms with pain and weakness in the bilateral thighs. Laboratory data showed hypophosphatemia, decreased tubular resorption of phosphate (TRP), a low 1,25-dihydroxyvitamin D level, and a high serum alkaline phosphatase level. Radiologic examinations revealed multiple lesions of osteomalacia in the ribs, and a small mass in the lower posterior mediastinum. After removal of the tumor, clinical symptoms disappeared and hypophosphatemia, decreased TRP, and the 1,25-dihydroxyvitamin D level were corrected. Microscopical examination revealed that the tumor was composed of mature adipose tissues, osseous tissues, and primitive stromal zones including osteoclast-like giant cells, non-mineralized woven bone, and various sized blood vessels. Patho-physiologic observations suggested that the tumor secreted some humoral substances inhibiting 25-hydroxyvitamin D-1 alpha-hydroxylase activity, renal phosphate resorption, and parathyroid hormone production.

Topics: Alkaline Phosphatase; Humans; Hypophosphatemia; Male; Mediastinal Neoplasms; Mesenchymoma; Middle Aged; Osteomalacia; Phosphates; Radionuclide Imaging; Ribs; Tomography, X-Ray Computed; Vitamin D