Regulation Of Phosphate Homeostasis Research Articles

GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity

GALNT3 encodes UDP-N-acetyl-alpha- d-galactosamine: polypeptide N-acetylgalactosaminyl-transferarase 3 (ppGalNacT3), a glycosyltransferase which has been suggested to prevent proteolysis of FGF23, a potent phosphaturic protein. Accordingly, loss-of-function mutations in GALNT3 cause hyperphosphatemic familial tumoral calcinosis (HFTC), a rare autosomal recessive disorder manifesting with increased kidney reabsorption of phosphate, resulting in severe hyperphosphatemia and widespread ectopic calcifications. Although these findings definitely attribute a role to ppGalNacT3 in the regulation of phosphate homeostasis, little is currently known about the factors regulating GALNT3 expression. In addition, the effect of decreased GALNT3 expression in peripheral tissues has not been explored so far. In the present study, we demonstrate that GALNT3 expression is under the regulation of a number of factors known to be associated with phosphate homeostasis, including inorganic phosphate itself, calcium and 1,25-dihydroxyvitamin D 3. In addition, we show that decreased GALNT3 expression in human skin fibroblasts leads to increased expression of FGF7 and of matrix metalloproteinases, which have been previously implicated in the pathogenesis of ectopic calcification. Thus, the present data suggest that ppGalNacT3 may play a role in peripheral tissues of potential relevance to the pathogenesis of disorders of phosphate metabolism.

Expression profiles of FGF23 in spermatozoa compared to normal and abnormal semen

OBJECTIVE: Several physiological factors and hormones play an important role in male infertility. Fibroblast growth factor 23 (FGF23), regulator of phosphate homeostasis, was identified as a humoral factor involved in the development of several hypophosphatemic diseases. Also FGF23 regulates vitamin D and phosphate in serum levels through mitogen extracellular kinase (MEK)/extracellular-regulated kinase (ERK) signaling pathway related with klotho as cofactor. Despite these reports, there is much uncovered knowledge about the physiology of FGF23 in human sperms.

Amelioration of the premature ageing‐like features of Fgf‐23 knockout mice by genetically restoring the systemic actions of FGF‐23

Genetic ablation of fibroblast growth factor 23 from mice (Fgf-23(-/-)) results in a short lifespan with numerous abnormal biochemical and morphological features. Such features include kyphosis, hypogonadism and associated infertility, osteopenia, pulmonary emphysema, severe vascular and soft tissue calcifications, and generalized atrophy of various tissues. To determine whether these widespread anomalies in Fgf-23(-/-) mice can be ameliorated by genetically restoring the systemic actions of FGF-23, we generated Fgf-23(-/-) mice expressing the human FGF-23 transgene in osteoblasts under the control of the 2.3 kb alpha1(I) collagen promoter (Fgf-23(-/-) /hFGF-23-Tg double mutants). This novel mouse model is completely void of all endogenous Fgf-23 activity, but produces human FGF-23 in bone cells that is subsequently released into the circulation. Our results suggest that lack of Fgf-23 activities results in extensive premature ageing-like features and early mortality of Fgf-23(-/-) mice, while restoring the systemic effects of FGF-23 significantly ameliorates these phenotypes, with the resultant effect being improved growth, restored fertility, and significantly prolonged survival of double mutants. With regard to their serum biochemistry, double mutants reversed the severe hyperphosphataemia, hypercalcaemia, and hypervitaminosis D found in Fgf-23(-/-) littermates; rather, double mutants show hypophosphataemia and normal serum 1,25-dihydroxyvitamin D(3) levels similar to pure FGF-23 Tg mice. These changes were associated with reduced renal expression of NaPi2a and 1 alpha-hydroxylase, compared to Fgf-23(-/-) mice. FGF-23 acts to prevent widespread abnormal features by acting systemically to regulate phosphate homeostasis and vitamin D metabolism. This novel mouse model provides us with an in vivo tool to study the systemic effects of FGF-23 in regulating mineral ion metabolism and preventing multiple abnormal phenotypes without the interference of native Fgf-23.

PHEX, FGF23, DMP1 and beyond

We aim to review the biological properties of novel molecules that are members of a kidney-bone axis involved in the regulation of phosphate homeostasis. In addition, we describe how an improved knowledge of the mechanisms leading to changes in renal phosphate handling may lead to the development of novel therapeutic approaches. As yet, eight genes involved in the regulation of phosphate homeostasis have been identified through genetic studies. A key protein in this regulatory pathway is FGF23, which is made by osteocytes and activates renal KLOTHO/FGFR1 receptor heterodimers to inhibit renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Gain-of-function mutations in FGF23, which render the hormone resistant to proteolytic cleavage, lead to increased phosphaturic activity. Furthermore, inactivating mutations in DMP1 and PHEX increase, through yet unknown mechanisms, FGF23 synthesis and thus enhance renal phosphate excretion. In contrast, loss-of-function mutations in FGF23 and KLOTHO, and abnormal O-glycosylation of FGF23 because of GALNT3 mutations, lead to diminished phosphate excretion. Extremely high levels of FGF23 are observed in chronic renal failure, which may contribute to the development of renal osteodystrophy. The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis, although it is not yet completely understood how these proteins interact, and additional proteins are likely to contribute to these regulatory events.

A Missense Mutation in the Sodium Phosphate Co-transporter Slc34a1 Impairs Phosphate Homeostasis

The sodium phosphate co-transporters Npt2a and Npt2c play important roles in the regulation of phosphate homeostasis. Slc34a1, the gene encoding Npt2a, resides downstream of the gene encoding coagulation factor XII (f12) and was inadvertently modified while generating f12(-/-) mice. In this report, the renal consequences of this modification are described. The combined single allelic mutant Slc34a1m contains two point mutations in exon 13: A499V is located in intracellular loop 5, and V528M is located in transmembrane domain 11. In addition to the expected coagulopathy of the f12(-/-) phenotype, mice homozygous for the double allelic modification (f12(-/-)/slc34a1(m/m)) displayed hypophosphatemia, hypercalcemia, elevated levels of alkaline phosphatase, urolithiasis, and hydronephrosis. Strategic cross-breedings demonstrated that the kidney-related pathology was associated only with autosomal recessive transmission of the slc34a1(m) gene and was not influenced by the simultaneous inactivation of f12. Npt2a[V528M] could be properly expressed in opossum kidney cells, but Npt2a[A499V] could not. These results suggest that a single amino acid substitution in Npt2a can lead to improper translocation of the protein to the cell membrane, disturbance of phosphate homeostasis, and renal calcification. Whether point mutations in the SLC34A1 gene can lead to hypophosphatemia and nephrolithiasis in humans remains unknown.

Hormonal regulation of phosphate homeostasis in goats during transition to rumination

Regulatory processes in phosphorus (P) homeostasis in small ruminants are quite different compared to monogastric animals. Adaptive responses of modulating hormones [parathyroid hormone (PTH) and calcitriol] to feeding variable amounts of P are lacking. Therefore, the aim of this study was to examine the influence of high dietary P intake (control diet: 4 g kg(-1) dry matter; high-P diet: 8 g kg(-1) dry matter) on the expression levels of PTH receptor (PTHR), vitamin D receptor (VDR) and Na+-dependent Pi transporters (NaPi II) in kidney and jejunum of goats starting rumination. After 3 months of feeding, plasma phosphate (Pi) and PTH concentrations were increased in the high-P diet group, whereas calcium and calcitriol were not changed. The intestinal Na+-dependent Pi transport capacity was not influenced by a high-P diet and the expression of jejunal VDR, PTHR and NaPi IIb was not modified. Interestingly, renal Na+-dependent Pi transport capacity was significantly reduced and concomitantly the expression of PTHR and NaPi IIa was decreased. In conclusion, the adaptive response of renal Pi reabsorption in goats, which were in transition from non-ruminant to ruminant stage was comparable to that of monogastric animals. In contrast, the modulation of the intestinal Pi absorption was like in adult ruminants.

BetaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c.

Fibroblast growth factor (FGF) 21, a structural relative of FGF23 that regulates phosphate homeostasis, is a regulator of insulin-independent glucose transport in adipocytes and plays a role in the regulation of body weight. It also regulates ketogenesis and adaptive responses to starvation. We report that in a reconstituted receptor activation assay system using BaF3 cells, which do not endogenously express any type of FGF receptor (FGFR) or heparan sulfate proteoglycan, FGF21 alone does not activate FGFRs and that betaKlotho is required for FGF21 to activate two specific FGFR subtypes: FGFR1c and FGFR3c. Coexpression of betaKlotho and FGFR1c on BaF3 cells enabled FGF21, but not FGF23, to activate receptor signaling. Conversely, coexpression of FGFR1c and Klotho, a protein related to betaKlotho, enabled FGF23 but not FGF21 to activate receptor signaling, indicating that expression of betaKlotho/Klotho confers target cell specificity on FGF21/FGF23. In all of these cases, heparin enhanced the activation but was not essential. In 3T3-L1 adipocytes, up-regulation of glucose transporter (GLUT) expression by FGF21 was associated with expression of betaKlotho, which was absent in undifferentiated 3T3-L1 fibroblasts. It is thus suggested that betaKlotho expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion.

Dentin Matrix Protein 1 (DMP1): New and Important Roles for Biomineralization and Phosphate Homeostasis

Previously, non-collagenous matrix proteins, such as DMP1, were viewed with little biological interest. The last decade of research has increased our understanding of DMP1, as it is now widely recognized that this protein is expressed in non-mineralized tissues, as well as in cancerous lesions. Protein chemistry studies have shown that the full length of DMP1, as a precursor, is cleaved into two distinct forms: the C-terminal and N-terminal fragments. Functional studies have demonstrated that DMP1 is essential in the maturation of odontoblasts and osteoblasts, as well as in mineralization via local and systemic mechanisms. The identification of DMP1 mutations in humans has led to the discovery of a novel disease: autosomal-recessive hypophosphatemic rickets. Furthermore, the regulation of phosphate homeostasis by DMP1 through FGF23, a newly identified hormone that is released from bone and targeted in the kidneys, sets a new direction for research that associates biomineralization with phosphate regulation.

Correlation among Hyperphosphatemia, Type II Sodium–Phosphate Transporter Activity, and Vitamin D Metabolism in Fgf‐23 Null Mice

Phosphate homeostasis is mostly regulated through humoral factors exerting direct or indirect effects on transporter proteins located in the intestine and kidney. Fibroblast growth factor 23 (FGF-23) is a major phosphate-regulating molecule, which can affect both renal and intestinal phosphate uptake to influence overall mineral ion homeostasis. We have found that Fgf-23 gene knockout mice (Fgf-23(-/-)) develop hyperphosphatemia that consequently leads to abnormal bone mineralization, and severe soft tissue calcifications. On the contrary, FGF-23 transgenic mice develop hypophosphatemia and produce rickets-like features in the mutant bone. Further studies using our Fgf-23(-/-) mice have identified an inverse correlation between Fgf-23, and vitamin D or NaPi2a; genomic elimination of either vitamin D or NaPi2a activities from Fgf-23(-/-) mice could reverse severe hyperphosphatemia to hypophosphatemia, and consequently could alter skeletal mineralization, suggesting that regulation of phosphate homeostasis in Fgf-23(-/-) mice is vitamin D- and NaPi2a-mediated process.

Can fibroblast growth factor 23 fine-tune therapies for diseases of abnormal mineral ion metabolism?

High serum fibroblast growth factor 23 (FGF-23) levels are associated with phosphaturia in several inherited and acquired human diseases. As FGF-23 actively regulates phosphate homeostasis, the author proposes that modulation of components of the FGF-23 signal transduction pathway might provide a novel therapeutic strategy for diseases of abnormal mineral ion metabolism.

Novel Regulators of Phosphate Homeostasis and Bone Metabolism

The regulation of phosphate homeostasis remains incompletely understood. Most insights into the underlying mechanisms were established by defining the molecular basis of different inherited disorders that are characterized by an abnormal regulation of phosphate homeostasis. Using this approach, three novel regulators were previously identified, namely PHEX (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome), fibroblast growth factor (FGF)-23 and UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Other studies had revealed heterozygous mutations in the sodium phosphate co-transporter NaPi-IIa as the cause of hypophosphatemia associated with hypercalciuria and osteoporosis, and homozygous or compound heterozygous mutations in NaPi-IIc were shown to cause hereditary hypophosphatemic rickets with hypercalciuria. Recently, positional cloning approaches furthermore led to the identification of homozygous inactivating mutations in dentin matrix protein 1 (DMP1) as the cause of an autosomal recessive form of hypophosphatemia. Using different immunometric assays, intact and C-terminal FGF-23 levels were found to be elevated in patients with oncogenic osteomalacia, and the tumors responsible for this disease showed increased expression of FGF-23 mRNA. Intact and C-terminal FGF-23 levels are furthermore elevated in patients with X-linked hypophosphatemia. This disorder is caused by inactivating PHEX mutations suggesting that this endopeptidase is somehow, most likely indirectly, involved in the metabolism of intact FGF-23. FGF-23 levels were also found to be elevated in some patients with ARHP indicating that the lack of DMP1 up-regulates expression of this phosphaturic hormone. The concentration of C-terminal FGF-23, but not of intact FGF-23, is significantly elevated in two forms of tumoral calcinosis (TC). One form of TC is caused by homozygous inactivating GALNT3 mutations implying that the encoded enzyme, which is involved in the initiation of O-glycosylation, is important for preventing cleavage of FGF-23 into biologically inactive fragments. The second form of tumoral calcinosis is caused by different homozygous FGF-23 mutations that affect conserved serine residues that may undergo O-glycosylation by GALNT3; the lack of this post-translational modification leads to an abnormal processing of FGF-23 and increased secretion of C-terminal fragments. It remains unknown whether and how the different phosphate-regulating proteins interact with each other and it appears very likely that additional proteins are involved in this process. It also remains unclear whether the dramatically elevated FGF-23 levels in patients with different stages of chronic kidney disease affect bone metabolism, particularly the mineralization of newly formed osteoid.

Phosphatonin

Previous studies have put forth a hypothesis that circulating phosphaturic factor (s) exist, and these factor (s) are generically called "phosphatonin" . Through the studies of patients with hypophosphatemic rickets/osteomalacia, FGF23 has emerged as an important candidate for phosphatonin. Discovery of FGF23 as an essential regulator of phosphate homeostasis has markedly improved our understanding of phosphate homeostasis and hypophosphatemic disorders. Elucidation of the mechanism of action of FGF23 as well as the role of PHEX on the development of FGF23 actions should further strengthen our knowledge on the regulation of phosphate homeostasis and pathogenesis of rickets/osteomalacia.

Hereditary hypophosphatemias: New genes in the bone–kidney axis (Review Article)

Hypophosphatemia due to isolated renal phosphate wasting is a genetically heterogeneous disease. Two new genes linked to two different forms of hereditary hypophosphatemias have recently been described. Autosomal recessive form of hypophosphatemic rickets was mapped to chromosome 4q21 and identified homozygous mutations in dentin matrix protein 1 (DMP1) gene, which encodes a non-collagenous bone matrix protein. Intact plasma levels of the phosphaturic protein FGF23 (fibroblast growth factor 23) were clearly elevated in some of the affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels, and suggesting that DMP1 may regulate FGF23 expression. Hereditary hypophosphatemic rickets with hypercalciuria is another rare disorder of autosomal recessive inheritance. Affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. The disease was mapped to a 1.6 Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaPi-IIc. This was the first demonstration that NaPi-IIc has a key role in the regulation of phosphate homeostasis. Thus, DMP1 and NaPi-IIc add two new members to the bone-kidney axis proposed since it was discovered that the first phosphatonin, FGF23, was of osteoblastic/osteocyte origin. This provides a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracelular matrix and the renal handling of phosphate.

Novel regulators of phosphate homeostasis and bone metabolism

The regulation of phosphate homeostasis remains incompletely understood. Most insights into the underlying mechanisms were established by defining the molecular basis of different inherited disorders that are characterized by an abnormal regulation of phosphate homeostasis. Using this approach, three novel regulators were previously identified, namely PHEX (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome), fibroblast growth factor (FGF)-23 and UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Other studies had revealed heterozygous mutations in the sodium phosphate co-transporter NaPi-IIa as the cause of hypophosphatemia associated with hypercalciuria and osteoporosis, and homozygous or compound heterozygous mutations in NaPi-IIc were shown to cause hereditary hypophosphatemic rickets with hypercalciuria. Recently, positional cloning approaches furthermore led to the identification of homozygous inactivating mutations in dentin matrix protein 1 (DMP1) as the cause of an autosomal recessive form of hypophosphatemia. Using different immunometric assays, intact and C-terminal FGF-23 levels were found to be elevated in patients with oncogenic osteomalacia, and the tumors responsible for this disease showed increased expression of FGF-23 mRNA. Intact and C-terminal FGF-23 levels are furthermore elevated in patients with X-linked hypophosphatemia. This disorder is caused by inactivating PHEX mutations suggesting that this endopeptidase is somehow, most likely indirectly, involved in the metabolism of intact FGF-23. FGF-23 levels were also found to be elevated in some patients with ARHP indicating that the lack of DMP1 up-regulates expression of this phosphaturic hormone. The concentration of C-terminal FGF-23, but not of intact FGF-23, is significantly elevated in two forms of tumoral calcinosis (TC). One form of TC is caused by homozygous inactivating GALNT3 mutations implying that the encoded enzyme, which is involved in the initiation of O-glycosylation, is important for preventing cleavage of FGF-23 into biologically inactive fragments. The second form of tumoral calcinosis is caused by different homozygous FGF-23 mutations that affect conserved serine residues that may undergo O-glycosylation by GALNT3; the lack of this post-translational modification leads to an abnormal processing of FGF-23 and increased secretion of C-terminal fragments. It remains unknown whether and how the different phosphate-regulating proteins interact with each other and it appears very likely that additional proteins are involved in this process. It also remains unclear whether the dramatically elevated FGF-23 levels in patients with different stages of chronic kidney disease affect bone metabolism, particularly the mineralization of newly formed osteoid.

Phosphatonins and the Regulation of Phosphate Homeostasis

Inorganic phosphate (P(i)) is required for energy metabolism, nucleic acid synthesis, bone mineralization, and cell signaling. The activity of cell-surface sodium-phosphate (Na(+)-P(i)) cotransporters mediates the uptake of P(i) from the extracellular environment. Na(+)-P(i) cotransporters and organ-specific P(i) absorptive processes are regulated by peptide and sterol hormones, such as parathyroid hormone (PTH) and 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)(2)D(3)), which interact in a coordinated fashion to regulate P(i) homeostasis. Recently, several phosphaturic peptides such as fibroblast growth factor-23 (FGF-23), secreted frizzled related protein-4 (sFRP-4), matrix extracellular phosphoglycoprotein, and fibroblast growth factor-7 have been demonstrated to play a pathogenic role in several hypophosphatemic disorders. By inhibiting Na(+)-P(i) transporters in renal epithelial cells, these proteins increase renal P(i) excretion, resulting in hypophosphatemia. FGF-23 and sFRP-4 inhibit 25-hydroxyvitamin D 1alpha-hydroxylase activity, reducing 1alpha,25(OH)(2)D(3) synthesis and thus intestinal P(i) absorption. This review examines the role of these factors in P(i) homeostasis in health and disease.

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

The Role of Mutant UDP-N-Acetyl-α-d-Galactosamine-Polypeptide N-Acetylgalactosaminyltransferase 3 in Regulating Serum Intact Fibroblast Growth Factor 23 and Matrix Extracellular Phosphoglycoprotein in Heritable Tumoral Calcinosis

Familial tumoral calcinosis (TC) results from disruptions in phosphate metabolism and is characterized by high serum phosphate with normal or elevated 1,25 dihydroxyvitamin vitamin D concentrations and ectopic and vascular calcifications. Recessive loss-of-function mutations in UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and fibroblast growth factor-23 (FGF23) result in TC. The objective of the study was to determine the relationship between GALNT3 and FGF23 in familial TC. We assessed the major biochemical defects and potential genes involved in patients with TC. Combination therapy consisted of the phosphate binder Sevelamer and the carbonic anhydrase inhibitor acetazolamide. We report a patient homozygous for a GALNT3 exon 1 deletion, which is predicted to truncate the encoded protein. This patient had high serum FGF23 concentrations when assessed with a C-terminal FGF23 ELISA but low-normal FGF23 levels when tested with an ELISA for intact FGF23 concentrations. Matrix extracellular phosphoglycoprotein has been identified as a possible regulator of phosphate homeostasis. Serum matrix extracellular phosphoglycoprotein levels, however, were normal in the family with GALNT3-TC and a kindred with TC carrying the FGF23 S71G mutation. The tumoral masses of the patient with GALNT3-TC completely resolved after combination therapy. Our findings demonstrate that GALNT3 inactivation in patients with TC leads to inadequate production of biologically active FGF23 as the most likely cause of the hyperphosphatemic phenotype. Furthermore, combination therapy may be effective for reducing the tumoral burden associated with familial TC.

The phosphatonins and the regulation of phosphate homeostasis

The phosphatonins and the regulation of phosphate homeostasis

SLC34A3 Mutations in Patients with Hereditary Hypophosphatemic Rickets with Hypercalciuria Predict a Key Role for the Sodium-Phosphate Cotransporter NaP i-IIc in Maintaining Phosphate Homeostasis

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis.

Regulation of Phosphate Homeostasis by MicroRNA in Arabidopsis

In this study, we reveal a mechanism by which plants regulate inorganic phosphate (Pi) homeostasis to adapt to environmental changes in Pi availability. This mechanism involves the suppression of a ubiquitin-conjugating E2 enzyme by a specific microRNA, miR399. Upon Pi starvation, the miR399 is upregulated and its target gene, a ubiquitin-conjugating E2 enzyme, is downregulated in Arabidopsis thaliana. Accumulation of the E2 transcript is suppressed in transgenic Arabidopsis overexpressing miR399. Transgenic plants accumulated five to six times the normal Pi level in shoots and displayed Pi toxicity symptoms that were phenocopied by a loss-of-function E2 mutant. Pi toxicity was caused by increased Pi uptake and by translocation of Pi from roots to shoots and retention of Pi in the shoots. Moreover, unlike wild-type plants, in which Pi in old leaves was readily retranslocated to other developing young tissues, remobilization of Pi in miR399-overexpressing plants was impaired. These results provide evidence that miRNA controls Pi homeostasis by regulating the expression of a component of the proteolysis machinery in plants.