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Peter S.n. Rowe - One of the best experts on this subject based on the ideXlab platform.
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A unified model for bone-renal mineral and energy metabolism.
Current opinion in pharmacology, 2015Co-Authors: Peter S.n. RoweAbstract:The beginning of the millennium saw the discovery of a new bone-Matrix protein, Matrix Extracellular Phosphoglycoprotein (MEPE) and an associated C-terminal motif called ASARM. This motif and other distinguishing features occur in a group of proteins called SIBLINGs. These proteins include dentin Matrix protein 1 (DMP1), osteopontin, dentin-sialophosphoprotein (DSPP), statherin, bone sialoprotein (BSP) and MEPE. MEPE, DMP1 and ASARM-motifs regulate expression of a phosphate regulating cytokine FGF23. Further, a trimeric interaction between phosphate regulating endopeptidase homolog X-linked (PHEX), DMP1, and α5β3-integrin that occurs on the plasma-membrane of the osteocyte mediates FGF23 regulation (FAP pathway). ASARM-peptides competitively inhibit the trimeric complex and increase FGF23. A second pathway involves specialized structures, Matrix vesicles pathway (MVP). This review will discuss the FAP and MVP pathways and present a unified model for mineral and energy metabolism.
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abnormal osteopontin and Matrix Extracellular Phosphoglycoprotein localization and odontoblast differentiation in x linked hypophosphatemic teeth
Connective Tissue Research, 2014Co-Authors: Benjamin Salmon, Peter S.n. Rowe, Claire Bardet, Benjamin R Coyac, Brigitte Baroukh, J Naji, Opsahl S Vital, Agnes Linglart, Marc D Mckee, Catherine ChaussainAbstract:AbstractMutations in phosphate-regulating gene (PHEX) lead to X-linked hypophosphatemic rickets (XLH), a genetic disease characterized by impaired mineralization in bones and teeth. In human XLH tooth dentin, calcospherites that would normally merge as part of the mineralization process are separated by unmineralized interglobular spaces where fragments of Matrix proteins accumulate. Here, we immunolocalized osteopontin (OPN) in human XLH teeth, in a three-dimensional XLH human dental pulp stem cell-collagen scaffold culture model and in a rat tooth injury repair model treated with acidic serine- and aspartate-rich motif peptides (ASARM). In parallel, Matrix Extracellular Phosphoglycoprotein (MEPE) immunolocalization and alkaline phosphatase (ALP) activity were assessed in XLH teeth. OPN was expressed by odontoblasts in the XLH models, and localized to the abnormal calcospherites of XLH tooth dentin. In addition, ALP activity and MEPE localization were abnormal in human XLH teeth, with MEPE showing an acc...
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Abnormal Presence of the Matrix Extracellular Phosphoglycoprotein-Derived Acidic Serine- and Aspartate-Rich Motif Peptide in Human Hypophosphatemic Dentin
The American journal of pathology, 2010Co-Authors: Tchilalo Boukpessi, Celine Gaucher, Matthew Garabedian, Peter S.n. Rowe, Benjamin Salmon, Thibaut Léger, Julie Le Faouder, Cyril Willig, Olivier Meilhac, Catherine ChaussainAbstract:Severe dental troubles are associated with X-linked hypophosphatemic rickets and are mainly related to impaired dentin mineralization. In dentin Matrix, Matrix Extracellular Phosphoglycoprotein (MEPE) may be protected from proteolysis by a specific interaction with PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome). The objective of our work was to determine whether PHEX impairment induces MEPE cleavage in dentin and the subsequent release of the C-terminal acidic serine- and aspartate-rich motif (ASARM) peptide, which is known to inhibit mineralization. By Western blot analysis, we explored dentin extracts from seven hypophosphatemic patients with mutations of the PHEX gene. A proteomic approach combining immunoprecipitation, surface-enhanced laser desorption/ionization-time of flight-mass spectrometry and Matrix-assisted laser desorption ionization-time of flight analysis of the samples completed this exploration. This study shows a 4.1-kDa peptide containing the MEPE-derived ASARM peptide in hypophosphatemic samples. The presence of ASARM was less marked in patients treated with 1-hydroxylated vitamin D and phosphate during growth. Moreover, recombinant ASARM implanted in a rat pulp injury model disturbed the formation of the reparative dentin bridge. These results suggest that abnormal MEPE cleavage occurs when PHEX activity is deficient in humans, the ASARM peptide may be involved in the mineralization defects and the PHEX-MEPE interaction may be indirect, as ensuring a better phosphate and vitamin D environment to the mineralizing dentin prevents MEPE cleavage.
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MEPE’s Diverse Effects on Mineralization
Calcified Tissue International, 2009Co-Authors: Adele L. Boskey, Valentin David, Phyllis Chiang, Alexis Fermanis, Jared Brown, Hayat Taleb, Peter S.n. RoweAbstract:Matrix Extracellular Phosphoglycoprotein (MEPE) is an inhibitor of mineralization in situ and in cell cultures where altered expression is associated with oncogenic osteomalacia and hypophosphatemic rickets. The purpose of this study was to determine whether the intact protein or the peptide(s) originating from this protein was responsible for the inhibition. The ability of the intact protein and the acidic, serine- and aspartate-rich MEPE-associated motif (ASARM) peptide to promote or inhibit de novo hydroxyapatite formation and growth of hydroxyapatite seed crystals, in both phosphorylated and dephosphorylated forms, was assessed at room temperature in a dynamic gel diffusion system at 3.5 and 5 days. The most effective nucleator concentration was also examined when associated with fibrillar type I collagen. The phosphorylated intact protein was an effective promoter of mineralization in the gelatin gel diffusion system, while the ASARM peptide was an effective inhibitor. When dephosphorylated both the intact protein and the ASARM peptide had no effect on mineralization. Associated with collagen fibrils, some of the effect of the intact protein was lost. This study demonstrates the importance of posttranslational modification for the site-specific activity of MEPE and its ASARM peptide.
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Matrix Extracellular Phosphoglycoprotein (MEPE) Is a New Bone Renal Hormone and Vascularization Modulator
Endocrinology, 2009Co-Authors: Valentin David, Aline Martin, Anne Marie Hedge, Peter S.n. RoweAbstract:Increased Matrix Extracellular Phosphoglycoprotein (MEPE) expression occurs in several phosphate and bone-mineral metabolic disorders. To resolve whether MEPE plays a role, we created a murine model overexpressing MEPE protein (MEPE tgn) in bone. MEPE tgn mice displayed a growth and mineralization defect with altered bone-renal vascularization that persisted to adulthood. The growth mineralization defect was due to a decrease in bone remodeling, and MEPE tgn mice were resistant to diet-induced renal calcification. MEPE protein-derived urinary ASARM peptides and reduced urinary Ca X PO4 product mediated the suppressed renal calcification. Osteoblastic cells displayed reduced activity but normal differentiation. Osteoclastic precursors were unable to differentiate in the presence of osteoblasts. In the kidney, NPT2a up-regulation induced an increase in phosphate renal reabsorption, leading to hyperphosphatemia. We conclude MEPE and MEPE-phosphate-regulating gene with homologies to endopeptidases on the X chromosome (MEPE-PHEX) interactions are components to an age-diet-dependent pathway that regulates bone turnover and mineralization and suppresses renal calcification. This novel pathway also modulates bone-renal vascularization and bone turnover.
Masato Tamura - One of the best experts on this subject based on the ideXlab platform.
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Regulation of mRNA expression of Matrix Extracellular Phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) by fibroblast growth factor 2 in cultures of rat bone marrow-derived osteoblastic cells
Endocrine, 2004Co-Authors: Gui Xia Zhang, Morimichi Mizuno, Kiyomi Tsuji, Masato TamuraAbstract:Matrix Extracellular Phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) is a recently isolated RGD-containing Matrix protein that acts as the tumor-derived phosphaturic factor in oncogenic hypophosphatemic osteomalacia. It is also highly expressed by osteoblasts and osteocytes. We examined the regulation of MEPE/OF45 mRNA expression in osteoblastic cells derived from high-density cultures of primary rat bone marrow stromal cells incubated with dexamethasone, β-glycerophosphate, and ascorbic acid. The level of MEPE/OF45 mRNA in these cells was down-regulated by the addition of fibroblast growth factor 2 (FGF2) for 48 h. These effects were observed in a dose-dependent manner between 2 and 10 ng/mL. FGF2 also reduced the expression of osteocalcin mRNA in these cells. In contrast, bone sialoprotein mRNA expression was increased by FGF2, while α1(I) procollagen mRNA expression was not altered. Additionally, neither Runx2 and osterix mRNA expression nor cell proliferation were affected by the addition of FGF2 in these high-density cultures, indicating that regulation by FGF2 may not be dependent on these transcription factors or on the proliferation of cells. Experiments using actinomycin D indicated that FGF2 decreased the stability of the MEPE/OF45 mRNA. Moreover, inhibition of a specific mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase kinase (MEK) by PD98059 blocked FGF2-regulated MEPE/OF45 expressions, indicating that this regulation requires the MAPK pathway. These results suggest that MEPE/OF45 gene is one of the targets of FGF2 and may play an important role during bone formation and calcification.
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regulation of mrna expression of Matrix Extracellular Phosphoglycoprotein mepe osteoblast osteocyte factor 45 of45 by fibroblast growth factor 2 in cultures of rat bone marrow derived osteoblastic cells
Endocrine, 2004Co-Authors: Gui Xia Zhang, Morimichi Mizuno, Kiyomi Tsuji, Masato TamuraAbstract:Matrix Extracellular Phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) is a recently isolated RGD-containing Matrix protein that acts as the tumor-derived phosphaturic factor in oncogenic hypophosphatemic osteomalacia. It is also highly expressed by osteoblasts and osteocytes. We examined the regulation of MEPE/OF45 mRNA expression in osteoblastic cells derived from high-density cultures of primary rat bone marrow stromal cells incubated with dexamethasone, β-glycerophosphate, and ascorbic acid. The level of MEPE/OF45 mRNA in these cells was down-regulated by the addition of fibroblast growth factor 2 (FGF2) for 48 h. These effects were observed in a dose-dependent manner between 2 and 10 ng/mL. FGF2 also reduced the expression of osteocalcin mRNA in these cells. In contrast, bone sialoprotein mRNA expression was increased by FGF2, while α1(I) procollagen mRNA expression was not altered. Additionally, neither Runx2 and osterix mRNA expression nor cell proliferation were affected by the addition of FGF2 in these high-density cultures, indicating that regulation by FGF2 may not be dependent on these transcription factors or on the proliferation of cells. Experiments using actinomycin D indicated that FGF2 decreased the stability of the MEPE/OF45 mRNA. Moreover, inhibition of a specific mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase kinase (MEK) by PD98059 blocked FGF2-regulated MEPE/OF45 expressions, indicating that this regulation requires the MAPK pathway. These results suggest that MEPE/OF45 gene is one of the targets of FGF2 and may play an important role during bone formation and calcification.
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Regulation of mRNA expression of Matrix Extracellular Phosphoglycoprotein (MEPE)/osteoblast/osteocyte factor 45 (OF45) by fibroblast growth factor 2 in cultures of rat bone marrow-derived osteoblastic cells
Endocrine, 2004Co-Authors: Gui Xia Zhang, Morimichi Mizuno, Kiyomi Tsuji, Masato TamuraAbstract:Matrix Extracellular Phosphoglycoprotein (MEPE)/ osteoblast/osteocyte factor 45 (OF45) is a recently isolated RGD-containing Matrix protein that acts as the tumor-derived phosphaturic factor in oncogenic hypophosphatemic osteomalacia. It is also highly expressed by osteoblasts and osteocytes. We examined the regulation of MEPE/OF45 mRNA expression in osteoblastic cells derived from high-density cultures of primary rat bone marrow stromal cells incubated with dexamethasone, β-glycerophosphate, and ascorbic acid. The level of MEPE/OF45 mRNA in these cells was down-regulated by the addition of fibroblast growth factor 2 (FGF2) for 48 h. These effects were observed in a dose-dependent manner between 2 and 10 ng/mL. FGF2 also reduced the expression of osteocalcin mRNA in these cells. In contrast, bone sialoprotein mRNA expression was increased by FGF2, while α1(I) procollagen mRNA expression was not altered. Additionally, neither Runx2 and osterix mRNA expression nor cell proliferation were affected by the addition of FGF2 in these high-density cultures, indicating that regulation by FGF2 may not be dependent on these transcription factors or on the proliferation of cells. Experiments using actinomycin D indicated that FGF2 decreased the stability of the MEPE/OF45 mRNA. Moreover, inhibition of a specific mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase kinase (MEK) by PD98059 blocked FGF2-regulated MEPE/OF45 expressions, indicating that this regulation requires the MAPK pathway. These results suggest that MEPE/OF45 gene is one of the targets of FGF2 and may play an important role during bone formation and calcification.
Shiguang Liu - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Endocrinology, 2007Co-Authors: Shiguang Liu, Peter S.n. Rowe, Jianping Zhou, Luke Vierthaler, Darryl L QuarlesAbstract:Inactivating PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome) mutations cause X-linked hypophosphatemia in humans and mice (Hyp) through overproduction of fibroblast growth factor 23 (FGF23) a phosphaturic factor, by osteocytes. Matrix Extracellular Phosphoglycoprotein (MEPE) is also elevated in Hyp and other hypophosphatemic disorders. In addition, the administration of an ASARM (acidic serine-aspartate rich MEPE-associated motif) peptide derived from MEPE causes phosphaturia and inhibits bone mineralization in mice, suggesting that MEPE also plays a role in phosphate homeostasis. Since recent studies found that MEPE binds specifically to PHEX in vitro, we tested the effect of recombinant-MEPE and its ASARM peptide on PHEX enzyme activity in vitro and FGF23 expression in bone marrow stromal cell cultures ex vivo. We found that both recombinant MEPE and synthetic phosphorylated ASARM peptide (ASARM-PO(4)) inhibit PHEX enzyme activities in an in vitro fluorescent-quenched PHEX enzyme activity assay. The ASARM-PO(4) peptide inhibits PHEX enzyme activity in a dose-dependent manner with a K(i) of 128 nM and V(max-i) of 100%. Recombinant MEPE also inhibits PHEX activity (K(i) = 2 nM and V(max-i) = 26%). Long-term bone marrow stromal cell cultures supplemented with 10 microM ASARM-PO(4) peptide resulted in significant elevation of FGF23 transcripts and inhibition of mineralization. These findings suggest that MEPE inhibits mineralization and PHEX activity and leads to increased FGF23 production. The resulting coordination of mineralization and release of a phosphaturic factor by MEPE may serve a physiological role in regulating systemic phosphate homeostasis to meet the needs for bone mineralization.
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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
The Journal of endocrinology, 2007Co-Authors: Shiguang Liu, Peter S.n. Rowe, Jianping Zhou, Luke Vierthaler, L. Darryl QuarlesAbstract:Inactivating PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome) mutations cause X-linked hypophosphatemia in humans and mice (Hyp) through overproduction of fibroblast growth factor 23 (FGF23) a phosphaturic factor, by osteocytes. Matrix Extracellular Phosphoglycoprotein (MEPE) is also elevated in Hyp and other hypophosphatemic disorders. In addition, the administration of an ASARM (acidic serine-aspartate rich MEPE-associated motif) peptide derived from MEPE causes phosphaturia and inhibits bone mineralization in mice, suggesting that MEPE also plays a role in phosphate homeostasis. Since recent studies found that MEPE binds specifically to PHEX in vitro, we tested the effect of recombinant-MEPE and its ASARM peptide on PHEX enzyme activity in vitro and FGF23 expression in bone marrow stromal cell cultures ex vivo. We found that both recombinant MEPE and synthetic phosphorylated ASARM peptide (ASARM-PO(4)) inhibit PHEX enzyme activities in an in vitro fluorescent-quenched PHEX enzyme activity assay. The ASARM-PO(4) peptide inhibits PHEX enzyme activity in a dose-dependent manner with a K(i) of 128 nM and V(max-i) of 100%. Recombinant MEPE also inhibits PHEX activity (K(i) = 2 nM and V(max-i) = 26%). Long-term bone marrow stromal cell cultures supplemented with 10 microM ASARM-PO(4) peptide resulted in significant elevation of FGF23 transcripts and inhibition of mineralization. These findings suggest that MEPE inhibits mineralization and PHEX activity and leads to increased FGF23 production. The resulting coordination of mineralization and release of a phosphaturic factor by MEPE may serve a physiological role in regulating systemic phosphate homeostasis to meet the needs for bone mineralization.
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Role of Matrix Extracellular Phosphoglycoprotein in the Pathogenesis of X-Linked Hypophosphatemia
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Shiguang Liu, Thomas A. Brown, Jianping Zhou, Zhousheng Xiao, Hani A. Awad, Farshid Guilak, L. Darryl QuarlesAbstract:X-linked hypophosphatemia (XLH), a disorder characterized by hypophosphatemia, impaired skeletal mineralization, and aberrant regulation of 1, 25(OH) 2 D 3 , is caused by inactivating mutations of Phex, which results in the accumulation of putative phosphaturic factors, called phosphatonins. Matrix Extracellular Phosphoglycoprotein (Mepe) is a proposed candidate for phosphatonin. The authors found that Hyp mice had increased expression of the MEPE and another phosphaturic factor, Fgf23. To establish MEPE’s role in the pathogenesis of the XLH, Mepe -deficient mice were back-crossed onto the Hyp mouse homologue of XLH and phenotypes of wild-type, Mepe −/− , Hyp , and Mepe −/− / Hyp mice were examined. Transfer of Mepe deficiency onto the Phex -deficient Hyp mouse background failed to correct hypophosphatemia and aberrant serum 1,25(OH) 2 D 3 levels. Increased Fgf23 levels in Hyp mice were not affected by superimposed Mepe deficiency. In addition, Mepe -deficient Hyp mice retained bone mineralization defects in vivo , characterized by decreased bone mineral density, reduced mineralized trabecular bone volume, lower flexural strength, and histologic evidence of osteomalacia; however, cultures of Hyp -derived bone marrow stromal cells in the absence of Mepe showed improved mineralization and normalization of osteoblast gene expression profiles observed in cells derived from Mepe -null mice. These results demonstrate that MEPE elevation in Hyp mice does not contribute to the hypophosphatemia associated with inactivating Phex mutations and is therefore not phosphatonin.
L. Darryl Quarles - One of the best experts on this subject based on the ideXlab platform.
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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
The Journal of endocrinology, 2007Co-Authors: Shiguang Liu, Peter S.n. Rowe, Jianping Zhou, Luke Vierthaler, L. Darryl QuarlesAbstract:Inactivating PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome) mutations cause X-linked hypophosphatemia in humans and mice (Hyp) through overproduction of fibroblast growth factor 23 (FGF23) a phosphaturic factor, by osteocytes. Matrix Extracellular Phosphoglycoprotein (MEPE) is also elevated in Hyp and other hypophosphatemic disorders. In addition, the administration of an ASARM (acidic serine-aspartate rich MEPE-associated motif) peptide derived from MEPE causes phosphaturia and inhibits bone mineralization in mice, suggesting that MEPE also plays a role in phosphate homeostasis. Since recent studies found that MEPE binds specifically to PHEX in vitro, we tested the effect of recombinant-MEPE and its ASARM peptide on PHEX enzyme activity in vitro and FGF23 expression in bone marrow stromal cell cultures ex vivo. We found that both recombinant MEPE and synthetic phosphorylated ASARM peptide (ASARM-PO(4)) inhibit PHEX enzyme activities in an in vitro fluorescent-quenched PHEX enzyme activity assay. The ASARM-PO(4) peptide inhibits PHEX enzyme activity in a dose-dependent manner with a K(i) of 128 nM and V(max-i) of 100%. Recombinant MEPE also inhibits PHEX activity (K(i) = 2 nM and V(max-i) = 26%). Long-term bone marrow stromal cell cultures supplemented with 10 microM ASARM-PO(4) peptide resulted in significant elevation of FGF23 transcripts and inhibition of mineralization. These findings suggest that MEPE inhibits mineralization and PHEX activity and leads to increased FGF23 production. The resulting coordination of mineralization and release of a phosphaturic factor by MEPE may serve a physiological role in regulating systemic phosphate homeostasis to meet the needs for bone mineralization.
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Role of Matrix Extracellular Phosphoglycoprotein in the Pathogenesis of X-Linked Hypophosphatemia
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Shiguang Liu, Thomas A. Brown, Jianping Zhou, Zhousheng Xiao, Hani A. Awad, Farshid Guilak, L. Darryl QuarlesAbstract:X-linked hypophosphatemia (XLH), a disorder characterized by hypophosphatemia, impaired skeletal mineralization, and aberrant regulation of 1, 25(OH) 2 D 3 , is caused by inactivating mutations of Phex, which results in the accumulation of putative phosphaturic factors, called phosphatonins. Matrix Extracellular Phosphoglycoprotein (Mepe) is a proposed candidate for phosphatonin. The authors found that Hyp mice had increased expression of the MEPE and another phosphaturic factor, Fgf23. To establish MEPE’s role in the pathogenesis of the XLH, Mepe -deficient mice were back-crossed onto the Hyp mouse homologue of XLH and phenotypes of wild-type, Mepe −/− , Hyp , and Mepe −/− / Hyp mice were examined. Transfer of Mepe deficiency onto the Phex -deficient Hyp mouse background failed to correct hypophosphatemia and aberrant serum 1,25(OH) 2 D 3 levels. Increased Fgf23 levels in Hyp mice were not affected by superimposed Mepe deficiency. In addition, Mepe -deficient Hyp mice retained bone mineralization defects in vivo , characterized by decreased bone mineral density, reduced mineralized trabecular bone volume, lower flexural strength, and histologic evidence of osteomalacia; however, cultures of Hyp -derived bone marrow stromal cells in the absence of Mepe showed improved mineralization and normalization of osteoblast gene expression profiles observed in cells derived from Mepe -null mice. These results demonstrate that MEPE elevation in Hyp mice does not contribute to the hypophosphatemia associated with inactivating Phex mutations and is therefore not phosphatonin.
Neal S. Fedarko - One of the best experts on this subject based on the ideXlab platform.
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small integrin binding ligand n linked glycoproteins siblings multifunctional proteins in cancer
Nature Reviews Cancer, 2008Co-Authors: Akeila Bellahcene, Vincenzo Castronovo, Larry W. Fisher, Kalu U E Ogbureke, Neal S. FedarkoAbstract:The family of glycophosphoproteins known as small integrin-binding ligand N-linked glycoproteins (SIBLINGs) are emerging as important players in malignant transformation, invasion and metastasis. Could these proteins be promising diagnostic and prognostic tools, as well as therapeutic targets? Numerous components and pathways are involved in the complex interplay between cancer cells and their environment. The family of glycophosphoproteins comprising osteopontin, bone sialoprotein, dentin Matrix protein 1, dentin sialophosphoprotein and Matrix Extracellular Phosphoglycoprotein — small integrin-binding ligand N-linked glycoproteins (SIBLINGs) — are emerging as important players in many stages of cancer progression. From their detection in various human cancers to the demonstration of their key functional roles during malignant transformation, invasion and metastasis, the SIBLINGs are proteins with potential as diagnostic and prognostic tools, as well as new therapeutic targets.
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Bone Sialoproteins and Breast Cancer Detection
2004Co-Authors: Neal S. FedarkoAbstract:Abstract : We have been studying a family of proteins that we have termed SIBLINGs for Small Integrin Binding LIgand N-linked Glycoproteins, that share similar structural domains, human chromosomal location, normal synthesis by skeletal tissue, and abnormal expression by neoplasms. The goal of the our research is to test whether SIBLINGs might be informative markers for breast cancer detection. To accomplish this goal we have developed competitive enzyme-linked immunosorbent assays (ELISAs) for the SIBLINGs bone sialoprotein (BSP), osteopontin (OPN), dentin Matrix protein-1 (DMP1), dentin sialophosphoprotein (DSPP) and Matrix Extracellular Phosphoglycoprotein (MEPE) . Sandwich-based ELISA assays have also been developed. When the competitive ELISAs were used to screen SIBLING protein levels, BSP and OPN exhibited the highest degree of sensitivity and specificity for the detection of breast cancer. When SIBLING levels in breast cancer patient-derived samples were segregated grossly by tumor type (lobular versus ductal), statistically significant differences between the two groups were observed. Microarray analysis of normal and breast cancer-derived mRNA samples found a similar elevated levels of elevated SIBLING expression and differences by tumor type. These results suggest that SIBLINGs may have utility as serum-based markers for breast cancer detection.
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Serum Levels of Matrix Extracellular Phosphoglycoprotein (MEPE) in Normal Humans Correlate with Serum Phosphorus, Parathyroid Hormone and Bone Mineral Density
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Alka Jain, Neal S. Fedarko, Michael T. Collins, Rebecca Gelman, M. A. Ankrom, M. Tayback, Larry W. FisherAbstract:Matrix Extracellular Phosphoglycoprotein (MEPE), a member of the Small Integrin Binding Ligand N-linked Glycoprotein (SIBLING) family, is primarily expressed in normal bone and has been proposed as a phosphaturic factor because of high expression and secretion in oncogenic hypophosphatemic osteomalacia tumors. In order to begin to address the role of MEPE in normal human physiology, we developed a competitive ELISA to measure serum levels of MEPE. The ELISA was used to characterize the distribution pattern in a population consisting of 114 normal adult subjects. The mean value of MEPE was 476 +/- 247 ng/ml and levels decreased significantly with increasing age. MEPE levels were also significantly correlated with serum phosphorus and parathyroid hormone (PTH). In addition, MEPE levels correlated significantly with measures of bone mineral density in the femoral neck and total hip in a subset of 50 elderly subjects. The results are consistent with MEPE being involved in phosphate and bone metabolism in a normal population.
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Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins.
Connective Tissue Research, 2003Co-Authors: Larry W. Fisher, Neal S. FedarkoAbstract:Bone sialoprotein (BSP), dentin Matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), enamelin (ENAM), Matrix Extracellular Phosphoglycoprotein (MEPE), and osteopontin (OPN) are glycophosphoproteins expressed in bones and/or teeth. Direct comparison of their amino acid sequences do not suggest that they belong to a single genetic family, but a detailed analysis of their chromosomal location and gene structure does. Analysis of human brain mRNA by RT-PCR has led to the discovery of two additional exons thereby making it more convincing that MEPE is a member of the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family. We propose that the members of this SIBLING family are extended, flexible proteins in solution that can facilitate the formation of a number of different complexes. For example, OPN can bridge complement Factor H to either an RGD-dependent integrin or to CD44 forming a membrane-bound complex that actively suppresses the alternate complement pathway. Two possible mechanis...
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Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins.
Connective tissue research, 2003Co-Authors: Larry W. Fisher, Neal S. FedarkoAbstract:Bone sialoprotein (BSP), dentin Matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), enamelin (ENAM), Matrix Extracellular Phosphoglycoprotein (MEPE), and osteopontin (OPN) are glycophosphoproteins expressed in bones and/or teeth. Direct comparison of their amino acid sequences do not suggest that they belong to a single genetic family, but a detailed analysis of their chromosomal location and gene structure does. Analysis of human brain mRNA by RT-PCR has led to the discovery of two additional exons thereby making it more convincing that MEPE is a member of the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family. We propose that the members of this SIBLING family are extended, flexible proteins in solution that can facilitate the formation of a number of different complexes. For example, OPN can bridge complement Factor H to either an RGD-dependent integrin or to CD44 forming a membrane-bound complex that actively suppresses the alternate complement pathway. Two possible mechanisms for inhibiting the lytic pathway of alternate complement are presented.