Phosphorylated acidic serine–aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity

Liu, Shiguang; Rowe, Peter; Vierthaler, Luke; Zhou, Jianping; Quarles, L. Darryl

doi:10.1677/joe.1.07059

Cited by 78 publications

(100 citation statements)

References 35 publications

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“…Studies of rodents showed that 1,25(OH) 2 D 3 inhibits MEPE production by osteoblasts 19 and that MEPE stimulates FGF-23 production in bone marrow stromal cells. 20 Indeed, a model of the complex interplay among FGF-23, 1,25(OH) 2 D 3 , and MEPE was described by Rowe and colleagues. Increased serum concentrations of MEPE have been reported in patients with X-linked hypophosphatemic rickets and in the Hyp mouse model of this disorder, 22 and MEPE was originally proposed as the factor responsible for hypophosphatemia, phosphaturia, and defective mineralization characteristic of X-linked hypophosphatemic rickets; however, a study of Hyp mice crossed onto a MEPE null background showed that MEPE is not the phosphaturic factor in this mouse model, because hypophosphatemia persisted.…”

Section: Discussionmentioning

confidence: 99%

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%

Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

Marks¹,

Churchill²,

Debnam³

et al. 2008

Journal of the American Society of Nephrology

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“…The following biochemical parameters were measured because of their novelty or correlation with bone parameters in cross-sectional prior studies: serum parathyroid hormone (PTH; commonly used to assess bone turnover abnormalities, which have been shown to be associated with changes in bone volume) (12), bone-specific alkaline phosphatase (BSAP) and procollagen type 1 N-terminal propeptide (P1NP; which are markers of osteoblastic activity) (13,14), tartrate-resistant acid phosphatase-5b (TRAP-5b; a marker of osteoclastic activity) (15), sclerostin (a protein produced by osteocytes [16,17] and expressed at bone formation sites [18,19]), Dickkopf-1 (DKK-1; found in bone and other tissues [20], and like sclerostin, it leads to increased bone formation and bone volume when knocked out) (21,22), and fibroblast growth factor 23 (FGF23; involved in mineral metabolism with a role in bone mineralization/remodeling) (23)(24)(25). In addition, serum calcium and phosphorus were measured.…”

Section: Determinations Of Blood Parametersmentioning

confidence: 99%

Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis

Malluche¹,

Davenport

Cantor³

et al. 2014

Clinical Journal of the American Society of Nephrology

122

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Background and objectives Use of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is controversial for diagnosing bone loss in CKD patients on dialysis. The alternative quantitative computed tomography (QCT) is expensive and requires high radiation exposure. This study compared the two techniques and evaluated serum biochemical parameters for prediction of bone loss.Design, setting, participants, & measurements This prospective study enrolled patients from dialysis centers throughout Kentucky. BMD of the spine and hip was measured at baseline and after 1 year by DXA and QCT. Customary and novel serum biochemical parameters were obtained at the same times, including calcium, phosphorus, whole and intact parathyroid hormone, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide, tartrate-resistant acid phosphatase-5b, Dickkopf-1, fibroblast growth factor, and sclerostin. Rates of detection of osteoporosis by DXA and QCT were compared. Correlations were calculated between baseline biochemical parameters and BMD at baseline and changes over 1 year. Multivariable regression was performed to adjust for age, sex, body mass index, and race.Results Eighty-one patients completed the study (mean age=52.6612.3 years, 56% men, 53% African American, and median dialysis vintage=41 months). At baseline, QCT and DXA of the spine identified similar rates of osteoporosis (13.6% and 13.6%), but at the hip, DXA identified more osteoporosis (22.2% versus 13.6%). At any site and by either method, 33.3% of the patients were osteoporotic. Baseline BMD correlated with sclerostin, intact parathyroid hormone, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase-5b, and fibroblast growth factor. At 1 year, hip QCT identified a higher number of patients experiencing bone loss (51.3%) than DXA (38.5%). After multivariable adjustment, baseline sclerostin and tartrate-resistant acid phosphatase-5b predicted bone loss measured by QCT of the hip; procollagen type 1 N-terminal propeptide predicted cortical spine bone gain by QCT.Conclusions QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and tartrate-resistant acid phosphatase-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis.

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“…Both systemic factors and local bone-derived factors seem to regulate FGF23 promoter activity (31). In this regard, circulating FGF23 levels are regulated by phosphate (32) and 1,25(OH) 2 D (31) as well as by the Phex endopeptidase located in osteocytes (7) and the SIBLING extracellular matrix proteins DMP1 (18,33) and MEPE (34). Phosphate loading in mice increases FGF23 levels (32), although the data in humans are conflicting (35)(36)(37).…”

Section: Regulation Of Fgf23mentioning

confidence: 99%

“…The targeted deletion of DMP1 increases FGF23 expression in osteocytes, leading to increased circulating levels (18). In contrast, MEPE administration causes phosphaturia, possibly by increasing FGF23 levels (34,40). In activating mutations of Phex, an endopeptidase that is located in osteocytes also results in increased transcription of FGF23 and elevated circulating levels (7).…”

Section: Regulation Of Fgf23mentioning

confidence: 99%

How Fibroblast Growth Factor 23 Works

Liu

Quarles

2007

Journal of the American Society of Nephrology

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366

341

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There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1 Fibroblast Growth Factor 23 Gene and Protein StructureThe fibroblast growth factor (FGF) family consists of 22 members with varied functions (2). FGF23 is an approximately 32-kD (251 amino acids) protein with an N-terminal region that contains the FGF homology domain and a novel 71-amino acid C-terminus that was originally discovered by homology-based PCR screening of a mouse embryonic cDNA library (3). The FGF23 gene is located on Chr 12p13 and is phylogenetically grouped with FGF19 and 21 gene products (2,3), with which it has approximately 24% and approximately 22% amino acid identities, respectively. FGF23 principally acts as a phosphaturic factor and suppressor of 1␣-hydroxylase activity in the kidney (4,5), making it functionally distinct from other members of this family. Tissue Expression and Function: Evidence for a Bone-Kidney AxisFGF23 is predominately expressed in osteocytes in bone (6,7), but it is also expressed in pericyte-like cells that surround the venous sinuses in the bone marrow, in the ventrolateral thalamic nucleus, and in thymus and lymph nodes (Figure 1). The relative contribution of these sites to circulating FGF23 levels is not known, but the high levels of expression in the osteocyte and that osteocytes are the most abundant cell in bone suggest that the serum levels of FGF23 are derived mainly from bone. In addition, the production of FGF23 by osteocytes, cells that are central to the regulation of osteoblast function and mineralization, likely has functional significance (8). In this regard, osteocytes secrete sclerostin, an inhibitor of bone formation and the phosphaturic factor FGF23, as well as other gene products, such as phosphate-regulating endopeptidase homolog, X-linked (Phex), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE), that regulate bone mineralization and FGF23 expression. Phex is a type I cell surface zinc metalloprotease that is involved in the regulation of FGF23 levels and is mutated in X-linked hypophosphatemic rickets (9). Both DMP1 and MEPE are glycophosphoproteins that belong to the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins. MEPE and DMP1 are predominately expressed in bones and/or teeth, where they respectively inhibit and induce mineralization of extracellular matrix (10). These associations suggest that osteocytes coordinate osteoblast-mediated bone formation with renal regulation of systemic phosphate homeostasis through the regu...

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Phosphorylated acidic serine–aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity

Cited by 78 publications

References 35 publications

Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

Matrix Extracellular Phosphoglycoprotein Inhibits Phosphate Transport

Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis

How Fibroblast Growth Factor 23 Works

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