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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.
J Endocrinol. 2007 Jan; 192(1):261-7.JE

Abstract

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.

Authors+Show Affiliations

The Kidney Institute, University of Kansas Medical Center, MS 3018, Kansas City, KS 66160, USA. sliu@kumc.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17210763

Citation

Liu, Shiguang, et al. "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, vol. 192, no. 1, 2007, pp. 261-7.
Liu S, Rowe PS, Vierthaler L, et al. 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. J Endocrinol. 2007;192(1):261-7.
Liu, S., Rowe, P. S., Vierthaler, L., Zhou, J., & Quarles, L. D. (2007). 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, 192(1), 261-7.
Liu S, et al. 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. J Endocrinol. 2007;192(1):261-7. PubMed PMID: 17210763.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Liu,Shiguang, AU - Rowe,Peter S N, AU - Vierthaler,Luke, AU - Zhou,Jianping, AU - Quarles,L Darryl, PY - 2007/1/11/pubmed PY - 2007/4/14/medline PY - 2007/1/11/entrez SP - 261 EP - 7 JF - The Journal of endocrinology JO - J. Endocrinol. VL - 192 IS - 1 N2 - 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. SN - 0022-0795 UR - https://www.unboundmedicine.com/medline/citation/17210763/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_ L2 - https://joe.bioscientifica.com/doi/10.1677/joe.1.07059 DB - PRIME DP - Unbound Medicine ER -