Inhibition of Intestinal Sodium‐dependent Inorganic Phosphate Transport by Fibroblast Growth Factor 23

Miyamoto, Ken‐ichi; Ito, Mikiko; Kuwahata, Masashi; Kato, Shigeaki; Segawa, Hiroko

doi:10.1111/j.1744-9987.2005.00292.x

Cited by 121 publications

(79 citation statements)

References 20 publications

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“…Using BBM vesicles, FGF-23 was previously shown to affect intestinal phosphate absorption; however, a regional effect has not been described. 13 Interestingly, our previous studies demonstrated that although there are striking differences in the regional profile of phosphate handling by the rat and mouse small intestine, in both rodent species, only the jejunum shows an increase in phosphate absorption in response to 1,25(OH) 2 D 3 . 6 This finding, together with the results of this study, suggests that the jejunum, at least in the rat, is of particular importance in the regulation of phosphate absorption.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that FGF-23 injection into normal mice causes a reduction in plasma 1,25(OH) 2 D 3 with concomitant inhibition of intestinal (using BBM vesicles) phosphate transport and NaPi-IIb protein expression. 13 Moreover, injection of FGF-23 into vitamin D receptor (VDR) null mice does not elicit any change in intestinal phosphate transport activity or in transporter expression, indicating that the action of FGF-23 depends on the VDR. 13 Conversely, administration of 1,25(OH) 2 D 3 to mice results in a dramatic increase in serum FGF-23 levels, and it has been proposed that these two hormones are part of a kidneyintestine-bone axis that controls phosphate balance.…”

mentioning

confidence: 99%

“…13 Moreover, injection of FGF-23 into vitamin D receptor (VDR) null mice does not elicit any change in intestinal phosphate transport activity or in transporter expression, indicating that the action of FGF-23 depends on the VDR. 13 Conversely, administration of 1,25(OH) 2 D 3 to mice results in a dramatic increase in serum FGF-23 levels, and it has been proposed that these two hormones are part of a kidneyintestine-bone axis that controls phosphate balance. 14 Our results demonstrate that MEPE can acutely inhibit both renal and intestinal phosphate transport and that MEPE might also play a role in normal phosphate balance; however, because MEPE fails to elicit changes in circulating parathyroid hormone (PTH), 1,25(OH) 2 D 3 , or FGF-23, its short-term action must occur via a mechanism that is independent of the classical modulators of phosphate homeostasis.…”

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confidence: 99%

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Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

Marks¹,

Churchill²,

Debnam³

et al. 2008

Journal of the American Society of Nephrology

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The role of putative humoral factors, known as phosphatonins, in phosphate homeostasis and the relationship between phosphate handling by the kidney and gastrointestinal tract are incompletely understood. Matrix extracellular phosphoglycoprotein (MEPE), one of several candidate phosphatonins, promotes phosphaturia, but whether it also affects intestinal phosphate absorption is unknown. Here, using the in situ intestinal loop technique, we demonstrated that short-term infusion of MEPE inhibits phosphate absorption in the jejunum but not the duodenum. Simultaneous measurement of urinary phosphate excretion suggests that the phosphaturic action of MEPE correlates with a significant reduction in the protein levels of the renal sodium-phosphate co-transporter NaPi-IIa in the proximal convoluted tubules of the outer renal cortex, assessed by Western blotting and immunohistochemistry. This short-term inhibitory effect of MEPE on renal and intestinal phosphate handling occurred without any changes in circulating levels of parathyroid hormone, 1,25-dihydroxyvitamin D 3 , or fibroblast growth factor 23. Taken together, these findings suggest that MEPE is a candidate phosphatonin involved in phosphate homeostasis, acting in both the kidney and the gastrointestinal tract. 19: 231319: -232019: , 200819: . doi: 10.1681 In the past 5 years, our understanding of the different mechanisms maintaining phosphate homeostasis has increased significantly, and recent attention has focused on the novel circulating factors called phosphatonins and their potential role in controlling renal phosphate excretion. These factors were originally identified in mesenchymal tumors from patients with tumor-induced osteomalacia, a disorder associated with renal phosphate wasting. So far they have been identified as fibroblast growth factor 23 (FGF-23), FGF-7, secreted frizzled related protein 4 (sFRP-4), and matrix extracellular phosphoglycoprotein (MEPE). All of them have been shown to inhibit renal phosphate absorption in vitro and in vivo; however, only FGF-23 and sFRP-4 are considered to play an important role in regulating (by inhibiting) the synthesis of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ; for comprehensive reviews, see references [1][2][3][4] ]. In contrast to the kidney, the role that these phosphatonins might have in regulating intestinal phosphate absorption has received limited attention. J Am Soc NephrolRecently, several groups, including our own, have begun to reevaluate the processes and regulatory mechanisms involved in intestinal phosphate absorption and the relationship of intestinal to renal phosphate handling. 5 Using both in vivo and in vitro techniques, we and others have found clear differences in the regional profile of intestinal phosphate absorption in rats compared with mice. 6,7 Indeed, the axial pattern of phosphate absorption in the rat is more similar to that reported in humans; therefore, the rat is perhaps a more appropriate an-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

See 1 more Smart Citation

Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

Marks¹,

Churchill²,

Debnam³

et al. 2008

Journal of the American Society of Nephrology

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“…However, when examined in mice, the effect of FGF-23 to suppress intestinal NaPi2b protein was vitamin D receptor dependent. 16 The net effect of PO4 loading on 1,25 (OH) 2 D in healthy humans is difficult to predict because hyperphosphatemia and increased FGF-23 were demonstrated to inhibit while increased PTH was shown to stimulate 1a-hydroxylase. [17][18][19] In addition, FGF-23 is positively regulated by 1,25(OH) 2 D, PTH, and Klotho.…”

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confidence: 99%

The Human Response to Acute Enteral and Parenteral Phosphate Loads

Scanni

vonRotz

Jehle

et al. 2014

Journal of the American Society of Nephrology

107

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The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; a-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads. Plasma phosphate (PO4) concentration is regulated within narrow limits and is the result of intestinal absorption, influx into and efflux from bone, renal excretion, and modest intestinal secretion. 1 Rapid changes in transcellular distribution are effected primarily by systemic acid-base equilibrium and hormones such as insulin and catecholamines. 2 1,25(OH) 2 D stimulates intestinal PO4 absorption, 4 while parathyroid hormone (PTH) and osteocytederived fibroblast growth factor-23 (FGF-23) are the best-characterized phosphaturic factors. Both inhibit proximal tubular sodium-dependent PO4 reabsorption (via Na/PO4 cotransport, NaPi2a and NaPi2c). 5,6 In addition, a-Klotho is a renal transmembrane and secreted protein that functions as an FGF-23 coreceptor and is phosphaturic independently of However, the relative roles of other phosphaturic agents, such as secreted frizzled related protein (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF-8 are not yet defined in humans.1,25(OH) 2 D, PTH, and FGF-23 regulate PO4 metabolism within a complex system of positive and negative feedback mechanisms (for review, see Bergwitz and Jüppner 8 ). Increases in plasma PO4 concentration stimulate PTH secretion, while proximal tubule 1a-hydroxylase and, therefore,

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“…In XLH, a loss-of-function mutation in PHEX leads to a decrease in Fa, resulting in an increase in FGF23a and the resultant renal phosphate wasting and inappropriately low 1,25(OH) 2 D levels. (55); therefore, it is not surprising that standard or even high doses of vitamin D had little effect on serum phosphorus and produced only small changes in urinary phosphate excretion in W.M. With megadoses of vitamin D (1,500,000 U/d), serum calcium rose, whereas serum phosphorus was unchanged (Figure 1).…”

Section: Other Potential Phosphatonin/minhibins In Xlhmentioning

confidence: 99%

The Journey From Vitamin D–Resistant Rickets to the Regulation of Renal Phosphate Transport

Levine¹,

Felsenfeld²

2009

Clinical Journal of the American Society of Nephrology

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(6) discuss the genetic and acquired disorders of hypophosphatemia and hyperphosphatemia in which FGF23 plays a role. Although Albright could not measure parathyroid hormone, he concluded on the basis of his studies that showed calcemic resistance to parathyroid extract in W.M. that hyperparathyroidism was present. Using a conceptual approach, we suggest that a defect in the skeletal response to parathyroid hormone contributes to hyperparathyroidism in XLH. Finally, at the end of the review, abnormalities in renal phosphate transport that are sometimes found in patients with polyostotic fibrous dysplasia are discussed.

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Inhibition of Intestinal Sodium‐dependent Inorganic Phosphate Transport by Fibroblast Growth Factor 23

Cited by 121 publications

References 20 publications

Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

The Human Response to Acute Enteral and Parenteral Phosphate Loads

The Journey From Vitamin D–Resistant Rickets to the Regulation of Renal Phosphate Transport

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