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Physiology 24: 17-25, 2009; doi:10.1152/physiol.00034.2008
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Physiology, Vol. 24, No. 1, 17-25, February 2009
© 2009 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Novel Mechanisms in the Regulation of Phosphorus Homeostasis

Theresa Berndt and Rajiv Kumar

Departments of Medicine, Biochemistry, and Molecular Biology, Nephrology Research, Mayo Clinic and Foundation, Rochester, Minnesota rkumar{at}mayo.edu


   Abstract
 
Phosphorus plays a critical role in diverse biological processes, and, therefore, the regulation of phosphorus balance and homeostasis are critical to the well being of the organism. Changes in environmental, dietary, and serum concentrations of inorganic phosphorus are detected by sensors that elicit changes in cellular function and alter the efficiency by which phosphorus is conserved. Short-term, post-cibal responses that occur independently of hormones previously thought to be important in phosphorus homeostasis may play a larger role than previously appreciated in the regulation of phosphorus homeostasis. Several hormones and regulatory factors such as the vitamin D endocrine system, parathyroid hormone, and the phosphatonins (FGF-23, sFRP-4, MEPE) among others, may play a role only in the long-term regulation of phosphorus homeostasis. In this review, we discuss how organisms sense changes in phosphate concentrations and how changes in hormonal factors result in the conservation or excretion of phosphorus.


   Phosphorus is Required for Diverse Biological Processes
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 Phosphorus is Required for...
Organs Involved in Phosphorus...
 The Regulation of Phosphorus...
 Conclusions
 References
 
Phosphorus plays a critical role in cellular biology (5). Many cellular processes require phosphorus in one form or another and include nucleic acid synthesis and metabolism (37), energy metabolism (42, 46), cellular signaling (38), membrane integrity (53, 58), muscle function (10, 33), enzyme activity (74), lipid metabolism (25), and bone mineralization (30). Phosphorus is present in virtually every bodily fluid. In human plasma or serum, phosphorus exists in the form of inorganic phosphorus or phosphate (Pi), lipid phosphorus, and phosphoric ester phosphorus. Total serum phosphorus concentrations range between 89 and 149 mg/l (2.87–4.81 mM), inorganic phosphorus (phosphate, Pi) concentrations between 25.6 and 41.6 mg/l (0.83–1.34 mM) (these change with age) (5), phosphoric ester phosphorus concentrations between 25 and 45 mg/dl (0.81–1.45 mM), and lipid phosphorus concentration between 69 and 97 mg/l (2.23–3.13 mM) (22). In mammals, bone contains substantial amount of phosphorus (approximately 10 g/100 g dry fat-free tissue); in comparison, muscle contains 0.2 g/100 g fat-free tissue, and brain contains 0.33 g/100 g fresh tissue (22).

Given its widespread distribution and critical role in vital cellular processes, it is not surprising that a deficiency of phosphorus results in clinical disease, including muscle weakness, rhabdomyolysis, impaired leukocyte function, and abnormal bone mineralization resulting in rickets or osteomalacia (34, 35, 64).


   Organs Involved in Phosphorus Homeostasis
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 Phosphorus is Required for...
 Organs Involved in Phosphorus...
The Regulation of Phosphorus...
 Conclusions
 References
 
The intestine and kidney play important roles in the absorption of phosphorus (in the form of Pi) from the diet and in the excretion of phosphorus (in the form of Pi) in the urine, respectively (4, 5). The quantitative aspects of phosphorus homeostasis in humans are shown in FIGURE 1Go (5). In states of neutral phosphorus balance, the amount of phosphorus absorbed in the intestine (13 mg · kg–1 ·· day–1,~1–1.5 g/24 h) is equivalent to the amount excreted in the urine. Various hormones and factors involved in the regulation of phosphorus homeostasis alter the efficiency of Pi absorption in the intestine or the reabsorption of Pi in the proximal tubule of the kidney. Pi absorption in the intestine is increased by 1{alpha},25(OH)2D3, although there is evidence for a 1{alpha},25(OH)2D3-independent increase in Pi transport during Pi deprivation that occurs in the absence of the 1{alpha},25(OH)2D3 receptor (17, 20, 21, 63, 72, 78, 81). In the kidney, Pi is reabsorbed along the proximal convoluted and proximal straight tubule, and Pi reabsorption is influenced by numerous factors, most importantly PTH (see Table 1Go) (4). In addition, the movement of Pi from the extracellular fluid into soft tissue and bone is controlled by numerous factors as well. Serum Pi concentrations can be altered significantly without changes in the absorption of Pi in the intestine or changes in excretion in the kidney.


Figure 1
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  		FIGURE 1. Phosphorus homeostasis in normal humans

Phosphorus homeostasis in normal humans (5).

 

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  		Table 1. Factors influencing phosphate absorption or reabsorption in the intestine and kidney
 

   The Regulation of Phosphorus Homeostasis
Top
 Phosphorus is Required for...
 Organs Involved in Phosphorus...
 The Regulation of Phosphorus...
Conclusions
 References
 
In the regulation of a metabolic process, it is important to consider 1) how environmental signals, to which the metabolic process responds, are sensed; 2) the nature of the responses that follow both with respect to changes in mediators and the effects of mediators in different organs; 3) temporal differences between the responses. As we will demonstrate, in the case of Pi, short-term responses that occur shortly (minutes to hours) after the feeding of a high Pi meal may play a larger role than previously appreciated. Furthermore, changes in the concentrations of hormones previously thought to be important in this regard the regulation of Pi homeostasis may only be of relevance during long-term changes (over a period of days) in dietary Pi intake.

Phosphate sensing and cellular responses to changes in phosphate concentrations in the environment
An important question regarding the regulation of phosphorus homeostasis is how the organism or individual senses changes in Pi concentrations in the environment and adjusts metabolic processes to accommodate such changes. Thus, in states of phosphorus deficiency, following a change in the concentrations of Pi, the acquisition and retention of Pi by the organism should be accelerated, whereas, in states of phosphorus excess, Pi acquisition and retention should be reduced. Individual cells or unicellular organisms sense changes in extracellular (or in some cases intracellular) Pi concentrations ({Delta}C) via specific "phosphate sensors" (41, 51, 76). The sensors, in turn, alter intracellular protein metabolism, generally by altering the phosphorylation state of intracellular proteins, and subsequent nuclear transcription events (FIGURE 2Go). Proteins synthesized in response to changes in gene transcription increase the efficiency with which phosphorus is retained by the cell and may be components of the cellular Pi sensor.


Figure 2
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  		FIGURE 2. Mechanisms by which cells and organisms respond to alterations in the extracellular phosphorus concentrations

IP, intestinal phosphatonin.

 
Phosphate sensing in cells
Responses to changes in extracellular phosphate in Escherichia coli and Saccharomyces cerevisiae are illustrative. For details, the reader is referred to two recent reviews (41, 51). Briefly, in E. coli, a set of proteins in the peri-plasmic membrane (PstS, PstC, PstA, and PstB in association with a protein PhoU) sense low concentrations of Pi in the external environment and enhance the uptake of Pi into the cell (41). Phosphorylation of histidine residues on a protein, PhoR, occurs; phosphorylated PhoR, in turn, phosphorylates PhoB on aspartase residues. Phosphorylated PhoB acts as a transcription factor by binding to DNA sequences known as "PHO boxes" to increase the transcription of genes in the Pho regulon. When Pi concentrations are no longer limiting, PhoR his de-phosphorylated and no longer phosphorylates PhoB; PhoB in its on-phosphorylated state is incapable of binding PHO boxes and activating transcription. Many of the genes in the Pho regulon help the organism adapt to changes in phosphorus concentrations. In Saccharomyces cerevisiae, when Pi in the environment is limited, the cyclin-dependent kinase (CDK) inhibitor Pho81 inactivates the Pho80-Pho85 complex (51). As a result, the transcription factor Pho4 is un-phosphorylated and active, leading to the induction of PHO genes, one of which encodes a protein, Pho84, that functions as a high-affinity Pi transporter and scavenges phosphate from the medium. When Pi is no longer limiting, Pho84 is degraded, and the transcription factor Pho4 is phosphorylated and exported from the nucleus to the cytoplasm, thereby turning off the expression of the PHO genes.

In multicellular organisms, the same sorts of processes that occur in unicellular organisms are likely to occur in cells that are present in the intestine and kidney, although the specific sensors and effector proteins are likely to be different. However, in multicellular organisms, it is likely that various signaling molecules are also elaborated by the sensing cell that subsequently alters of the efficiency of Pi absorption in other organs in a hormonal or autocrine/paracrine fashion. Markowitz et al. have shown that renal epithelial cells maintained in culture are capable of responding directly to changes in environmental Pi concentrations by altering the efficiency of Pi uptake (48). The authors grew opossum kidney cells in high or low Pi media and were able to show changes in the efficiency of sodium-dependent Pi absorption within 1 h of changing medium Pi concentrations. Given the manner in which the cells were grown, it is unlikely that changes in a hormonal factor were involved in changing the efficiency of sodium-dependent Pi uptake. Several investigators have suggested that intestinal cells may also respond directly to changes in Pi concentrations by altering the efficiency of Pi transport (45, 57, 63). Others have demonstrated that nonepithelial cells such as osteoblasts and marrow stromal cells are capable of responding to changes in medium Pi concentrations by altering BMP-4 expression, Runx2/Cbfa1 localization, and alkaline phosphatase secretion (26–28). These results would suggest the presence of a phosphate sensor in mammalian cells. However, the exact biochemical nature of this sensor is not known.

Phosphate sensing in animals
Martin and colleagues demonstrated the presence of phosphate signaling in the gastrointestinal tract and the parathyroid gland in rodents (50). Uremic animals were fed a high-phosphate diet for 4 wk and were then administered a low-phosphate diet on the day of the experiment. There was a rapid reduction in serum concentrations of parathyroid hormone within 2 h without changes in serum calcium. Serum phosphate concentrations decreased. When uremic rats fed a high-phosphate diet were gavaged with a high-phosphate diet on the day of the experiment, PTH levels increased with only modest changes in serum phosphate during the first 30 min of the experiment. Phosphonoformic acid, a phosphorus uptake inhibitor, also rapidly increased PTH concentrations with no significant changes in serum phosphorus. The administration of intravenous phosphate was associated with a rapid increase in PTH with no changes in serum calcium and modest increases in serum phosphorus. These data would suggest the presence of a phosphate sensor in the intestine and in the parathyroid gland as well. The nature of the sensor is not known. Sensors involved in calcium and PTH homeostasis, such as the calcium-sensing receptor (12), are present in the intestine where they may play a role in sensing concentration of luminal amino acids (16). Whether the Ca-sensing receptor or a similar G-protein-coupled receptor is involved in sensing phosphate remains unknown. Our laboratory performed experiments in which phosphate was administered into the duodenum of intact or parathy-roidectomized rats (6). Changes in the fractional excretion of phosphate were examined 5, 10, 20, and 30 min after the infusion of phosphate into the duodenum. In the intact rats, we observed a rapid increase in the fractional excretion of phosphate in the kidney without changes in serum phosphate concentrations. Rats infused sodium chloride into the duodenum showed no changes in the fractional excretion of phosphate. In thyro-parathyroidectomized rats, there was a similar increase in the fractional excretion of phosphate following the administration of intra-duodenal phosphate. The latter experiments clearly show that increases in the renal fractional excretion of phosphate following intra-duodenal phosphate infusion are independent of PTH. We also measured serum concentrations of the phosphaturic peptides, PTH, FGF-23, and sFRP-4, in both intact and parathyroidectomized rats following the infusion of intra-duodenal phosphate or intra-duodenal sodium chloride. There were no significant differences between the serum concentrations of these three phosphaturic peptides throughout the experiment. Our data show that there is a sensor for phosphate in the intestine that causes an increase in the fractional excretion of phosphate in the kidney within a short period of time following the exposure of the intestinal mucosa to increased phosphate concentrations (FIGURE 3Go). Furthermore, the response that occurs in the kidney is not mediated by any of the known phosphaturic factors that regulate the excretion of phosphorus in the kidney. An important caveat is that concentrations of MEPE and FGF-7 were not measured, and it is not known whether concentrations of these phosphaturic substances increased following the instillation of Pi into the intestine. It should also be kept in mind that the amount of Pi instilled in the intestine was large compared with normal dietary Pi intake. What then is the signal emanating in the intestine that tells the kidney to increase the fractional excretion of phosphate? Renal nerves are not involved in this process since we demonstrated that renal denervation did not alter the phosphaturic response following the intra-duodenal infusion of phosphate. We next prepared homogenates of the duodenum and infused filtered proteins derived from the intestine into rats. We demonstrated the presence of a factor in the duodenal mucosa that was capable of inducing phosphaturia in the intact rats. Taken together, the data show that the intestine senses an increase in luminal phosphate concentrations and releases a substance into the circulation that inhibits renal phosphate reabsorption (FIGURE 3Go).


Figure 3
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  		FIGURE 3. Intestinal phosphate sensing increases the fractional excretion of phosphorus in the kidney following increases in intestinal luminal phosphate concentrations by the release of an intestinal mediator ("intestinal phosphatonin")

 
Experiments performed by Segawa and colleagues have shown that the intestine is capable of responding to changes in dietary phosphate independent of vitamin D (63). In vitamin D receptor knockout mice, these investigators were able to demonstrate the upregulation of the sodium-phosphate cotransporter IIB by the low dietary phosphate. This would suggest that intestinal cells have the ability to detect changes in luminal phosphate concentrations and increase the uptake of phosphate via upregulation of the synthesis of the sodium-phosphate cotransporter.

Thus information reviewed so far would support 1) the capacity of unicellular organisms to respond to changes in environmental phosphate; 2) the capacity of intestinal cells and renal cells to respond directly to changes in phosphate concentrations in the medium and the capacity of the intestinal cells to respond to changes in dietary phosphate content; and 3) the capacity of the intestine and kidney to alter phosphate handling independent of 1,25-dihydroxy vitamin D, PTH and, the phosphatonins.

PTH, the vitamin D endocrine system, and the phosphatonins in the regulation of phosphate homeostasis
What is the role of the vitamin D endocrine system, PTH, and the phosphatonins in the regulation of phosphate transport? The role of these factors in regulating phosphate concentrations is shown in FIGURE 4Go. The phosphatonins, FGF-23 and sFRP-4 (3, 7, 43, 56, 62, 65–68), decrease and IGF-1 increases (18) the activity of the 25-hydroxy vitamin D 1{alpha}-hydroxylase ("growth factors" in FIGURE 4Go). They may, if one accepts the debatable proposition that their levels are modulated by serum phosphate concentrations (see discussion below), also directly modulate renal phosphate reabsorption (13, 44, 52, 54, 71).


Figure 4
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  		FIGURE 4. Adaptations to changes in dietary phosphate

Adaptations to changes in dietary phosphate (5).

 
Animals fed a low-phosphate diet have decreased serum phosphate concentrations that are associated with a reciprocal increase in circulating plasma calcium concentrations. The increase in plasma calcium concentrations inhibits PTH release, which in turn reduces the renal excretion of phosphate. Inorganic phosphate may also directly influence PTH release (50). Additionally, a low-phosphate diet and reductions in serum Pi are associaed with increased 1{alpha},25(OH)2D3 synthesis as a result of stimulation of 25-hydroxy vitamin D 1{alpha}-hydroxylase activity (72, 77, 78). It is important to note that the increases in 25-hydroxy vitamin D 1{alpha}-hydroxylase activity that occur in animals fed a low-phosphate diet are independent of PTH, since they occur in parathyroidectomized animals. Conversely, when animals are fed a high-phosphate diet, serum calcium concentrations decrease and PTH release is increased. Given the importance of phosphate ions in cellular function, a variety of other mechanisms must exist to maintain phosphate balance. For example, dietary phosphate deprivation markedly decreases Pi excretion, yet this adaptation to decreases in Pi intake is similar in the presence and absence of PTH (73).

The "phosphatonins" induce renal phosphate wasting in patients with tumor-induced osteomalacia (TIO) (14, 23). Such patients typically exhibit low serum phosphate concentrations, normal or slightly low serum calcium concentrations, normal PTH concentrations, low or inappropriately normal serum 1{alpha},25(OH)2D concentrations, renal phosphate wasting, and a defect in bone mineralization. Conditioned media from tumors associated with this syndrome produce substances that inhibit sodium-dependent Pi transport in cultured opossum kidney cells. Of note, this phenotype is also observed in patients with autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), and autosomal recessive hypophosphatemic rickets (ARHR), and the serum of such patients also contains phosphatonin-like activity (9, 39, 62, 64). Subsequent work by several laboratories has shown that factors such as fibroblast growth factor (FGF-23), secreted frizzled-related protein (sFRP-4), fibroblast growth factor (FGF-7), and MEPE are present in these tumors and may contribute to the phosphaturia associated with this syndrome (3, 5, 9, 11, 19, 59, 60, 67). Identification of these phosphatonin molecules has led to the recognition that these proteins are also involved in numerous pathophysiological conditions associated with phosphate wasting and may be important regulators of phosphate homeostasis (Table 2Go) (64). Although there is no question as to the importance of these factors in the pathophysiology of phosphate in the various disorders described, it remains somewhat uncertain as to whether the phosphatonins play a role in normal phosphate homeostasis.


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  		Table 2. The pathophysiology of disorders of phosphate homeostasis associated with altered phosphatonin production/circulating concentrations (64)
 
The most extensively studied phosphatonin is FGF-23, a 251-amino acid secreted protein (1, 5, 8, 9). Recombinant FGF-23 administered intraperitoneally to mice or rats induces phosphaturia and inhibits 25-hydroxy vitamin D 1{alpha}-hydroxylase activity (1, 5, 8, 9). The minimal sequence needed for phosphaturic activity resides between amino acids 176 and 210 (8). Transgenic animals overexpressing FGF-23 are hypophosphatemic, phosphaturic, and show the presence of rickets and reduced serum 1{alpha},25(OH)2D concentrations or 25-hydroxy vitamin D 1{alpha}-hydroxylase activity (2, 43, 68). Conversely, mice in which the FGF-23 gene has been ablated demonstrate hyperphosphatemia, reduced phosphate excretion, markedly elevated serum 1{alpha},25(OH)2D concentrations and renal 25-hydroxy vitamin D 1{alpha}-hydroxylase mRNA expression, vascular calcification, and early mortality (65, 69). The ablation of the vitamin D receptor in FGF-23-null mice has been reported to rescue this phenotype, supporting an important role for vitamin D in the pathogenesis of the abnormal phenotype seen in FGF-23-null mice (70). Feeding FGF-23-null mice a low-phosphate diet results in decreased serum Pi and a reversal of vascular calcification. When the FGF-23-null mice were fed a vitamin D-deficient diet, serum Pi and vascular calcification were improved minimally (75). FGF-23 binds and signals through FGF receptors 1c, 3c, and FGFR4 (40), although this has not been established in mice in vivo (47). A co-receptor, klotho, is necessary for FGF-23 to exhibit bioactivity (40, 80). The role of klotho in FGF-23 signaling is supported by the observation that klotho knockout mice have a phenotype identical to that of FGF-23 knockout mice (79).

From a physiological perspective, it would be appropriate for FGF-23 concentrations to be regulated by the intake of dietary phosphorus and by serum phosphate concentrations. In humans, in the short-term (over a period of hours), the feeding of meals containing increasing amounts of phosphate does not increase serum FGF-23 concentrations, even though the previously administered meal induces a robust and dose-dependent phosphaturia (52). Nishida et al. have shown that the administration of high-phosphate diets to humans increases the fractional excretion of phosphate within an hour of the ingestion of a high-phosphate meal (52). In this study, there were modest increases in PTH and no biologically relevant changes in FGF-23 after administration of a high-phosphate diet (52). Ito et al. also failed to demonstrate an effect of infused Pi on FGF-23 concentrations (31). Likewise, in a study by Larsson et al., human subjects fed normal, high-, or low-phosphate diets for a period of 72 h showed no differences in serum FGF-23 concentrations (44). Other studies conducted over a period of days, however, have shown changes in serum FGF-23 concentrations following alterations in the content of phosphate in the diet. For example, Ferrari et al. administered a high- or a low-phosphate diet to humans over several days. Concomitant changes in dietary calcium designed to minimize changes in PTH were also made. Modest decreases or increases of serum FGF-23 within normal range were observed following the intake of a low- or high-phosphate diet, respectively (24). Others have shown similar changes when dietary phosphate is altered over a period of several weeks (13). In mice, Perwad et al. showed that a high-phosphate diet increased and a low-phosphate diet decreased serum FGF-23 levels in these animals within 5 days of changing dietary phosphate intake (55). The changes in serum FGF-23 correlated with changes in serum phosphate concentrations. Studies from our laboratory performed in rats fed a low-, normal, or high-phosphate diet demonstrated that serum FGF-23 levels significantly decrease in animals fed a low-phosphate diet and increase in animals fed a high-phosphate diet within 24 h of altering dietary phosphate intake but do not correlate with serum phosphate in the animals fed a high-phosphate diet (71). These data suggest that early and rapid changes in renal phosphate excretion occur following ingestion of a high-phosphate meal and are independent of FGF-23.

FGF-23 synthesis is regulated by 1{alpha},25(OH)2D. Increasing doses of 1{alpha},25(OH)2D increase FGF-23 concentrations in the serum within 24 h, but statistically significant changes are observed 4 h after 1{alpha},25(OH)2D treatment (36, 61). In the physiological sense, it is possible that FGF-23 is a negative feedback regulator of the 25-hydroxy vitamin D 1{alpha}-hydroxylase enzyme.

The Wnt antagonist secreted frizzled related protein-4 (sFRP-4) is highly expressed in tumors associated with renal phosphate wasting and osteomalacia (19). Recombinant sFRP-4 is phosphaturic in rats and prevents the upregulation of the 25-hydroxy vitamin D 1{alpha}-hydroxylase enzyme seen in the presence of hypophosphatemia (3). sFRP-4 decreases Na+-Pi co-transporter abundance in the brush border membrane of the proximal tubule and reduces the surface expression of the Na+-Pi IIa co-transporter in proximal tubules of the kidney as well as on the surface opossum kidney cells (7). sFRP-4 expression is increased in bone samples and serum from X-linked hypophosphatemic mice and in mice with a global knockout of the phex gene but not in mice in which the phex gene has been knocked out in bone alone (82). sFRP-4 protein concentrations are increased in the kidneys of rats fed a high-phosphate diet for 2 wk but not in animals fed a low-phosphate diet, suggesting a possible role for sFRP-4 during increases in phosphate intake (71). This suggests that sFRP-4 concentrations are altered in the kidney of animals fed a high-phosphate diet and could play a role in the long-term adaptations to high phosphate intake.

Matrix extracellular phosphoglycoprotein (MEPE) is abundantly overexpressed and found in tumors associated with renal phosphate wasting and osteomalacia (59). Recombinant MEPE is phosphaturic and reduces serum phosphate concentrations when administered to mice in vivo (60). The protein inhibits sodium-dependent phosphate uptake in opossum kidney cells. The protein has also been demonstrated to reduce intestinal Pi absorption directly (49). MEPE also inhibits bone mineralization in vitro, and MEPE-null mice have increased bone mineralization (29). Thus it is possible that MEPE is important in the pathogenesis of hypophosphatemia in renal phosphate wasting observed in patients with TIO. However, MEPE infusion does not recapitulate the defect in vitamin D metabolism seen in patients with TIO (60). Infusion of MEPE reduces serum phosphate concentrations, and serum 1{alpha},25(OH)2D concentrations increase following MEPE, as would be expected in the face of hypophosphatemia. Thus, in patients with TIO, it is likely that MEPE contributes to the hypophosphatemia, but other products such as FGF-23 and sFRP-4 inhibit 1{alpha},25(OH)2D concentrations by inhibiting the activity of the 25-hydroxy vitamin D 1{alpha}-hydroxylase. MEPE may play a role in the pathogenesis of X-linked hypophosphatemic rickets in which there is phosphate wasting and evidence for a mineralization defect that is independent of low phosphate concentrations in the extracellular fluid (82). MEPE expression is increased in mice with the Hyp mutation and mice with a global knockout of the phex gene but not in mice with a bone-specific knockout of the phex gene. It is not known whether MEPE is regulated by phosphate concentrations, although Jain et al. have demonstrated that it is correlated with serum Pi concentration in normal humans (32).

Another growth factor, FGF-7, also known as keratinocyte growth factor, is overexpressed in tumors associated with phosphate wasting and osteomalacia (15). FGF-7 inhibits sodium-dependent phosphate transport in OK cells, and we have demonstrated that FGF-7 inhibits renal phosphate reabsorption in vivo. FGF-7 is present in normal plasma and is significantly increased in patients with renal failure (personal observations). Whether or not FGF-7 is regulated by phosphate concentrations is unknown.


   Conclusions
Top
 Phosphorus is Required for...
 Organs Involved in Phosphorus...
 The Regulation of Phosphorus...
 Conclusions
References
 
The regulation of phosphate transport in vivo should be thought of in terms of rapid, short-term adaptive processes that occur within a timeframe of a few hours after the administration of a meal containing large amounts of phosphate. These processes involve phosphate sensing in the intestine and the elaboration of novel factors that alter the efficiency of phosphate transport in the kidney and possibly directly in the intestine itself. The more long-term adaptations to changes in phosphate transport are likely to be mediated by the vitamin D endocrine system and PTH. The role of the phosphatonins in normal human physiology remains to be established, although there is no question as to their importance in the pathophysiology of diseases associated with alterations in serum phosphate homeostasis.


   Acknowledgments
 
This review was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-076829 and DK-65830 to R. Kumar.


   References
Top
 Phosphorus is Required for...
 Organs Involved in Phosphorus...
 The Regulation of Phosphorus...
 Conclusions
 References
 

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