Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

Abstract

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-

ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate

“…Indeed, several studies report FGF23 interacts with KLOTHO to directly suppress renal NPT2A expression in the brush border of renal proximal convoluted tubules (45). Likewise, ASARM peptides (in vitro) and MEPE (in vivo and in vitro) directly inhibit Na-dependent P i uptake in renal cells (14,36,49,51,52,56).…”

“…For example, several studies confirm fulllength MEPE inhibits intestinal/renal phosphate transport and mineralization in vivo and in vitro (14,36,49,52,56). These studies consist of bolus injections or direct perfusion in rats and mice using recombinant MEPE protein.…”

The importance of the SIBLING family of proteins on skeletal mineralisation and bone remodelling

“…Additionally, the accumulation of ASARM peptides can directly inhibit Na C -dependent P i uptake in the kidney, as has been shown both in vivo and in vitro, thus exacerbating the upregulation of FGF23 expression, the downregulation of 1,25(OH) 2 D 3 and the inhibition of hypophosphataemia observed in XLH, ARHR and ADHR , Dobbie et al 2008, Marks et al 2008, David et al 2010, Shirley et al 2010. The decrease in 1,25(OH) 2 D 3 provides a feedback loop for increased PHEX expression through the increased expression of a 100 kDa transcription factor, a requirement for this PHEX expression (Ecarot & Desbarats 1999).…”

“…The administration of the MEPE-ASARM peptide in vitro and in vivo can inhibit the uptake of P i . This is likely through a decreased expression of the type II sodium-dependent P i cotransporter NPT2a, or through the promotion of FGF23 expression, a potent inhibitor of P i (Liu et al 2007, Dobbie et al 2008, Marks et al 2008, Martin et al 2008, David et al 2010, Shirley et al 2010. It has, however, been suggested that MEPE may have a direct effect on matrix mineralisation outwith the supply and demand of P i .…”

The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels

“…sFRP4 acutely downregulates renal phosphate reabsorption and NaPi-IIa abundance in rat kidney [11], however, mice lacking sFRP4 adapt normally to changes in phosphate intake [18]. MEPE reduces renal phosphate reabsorption [21,31] and MEPE deficient mice display hyperphosphatemia with elevated expression of NaPi-IIa consistent with a phosphaturic role of MEPE [20]. However, the role of MEPE in the acute renal adaption to changes in dietary phosphate intake has not been determined.…”