title: Abnormal presence of the matrix extracellular phosphoglycoprotein-derived acidic serine- and aspartate-rich motif peptide in human hypophosphatemic dentin.
abstract: 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.
authors.affiliation: Faculté de Chirurgie Dentaire, Université Paris Descartes, EA 2496, Montrouge, France.
authors.forename: Tchilalo
authors.initials: T
authors.lastname: Boukpessi
authors.forename: Celine
authors.initials: C
authors.lastname: Gaucher
authors.forename: Thibaut
authors.initials: T
authors.lastname: Léger
authors.forename: Benjamin
authors.initials: B
authors.lastname: Salmon
authors.forename: Julie
authors.initials: J
authors.lastname: Le Faouder
authors.forename: Cyril
authors.initials: C
authors.lastname: Willig
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rowe
authors.forename: Michèle
authors.initials: M
authors.lastname: Garabédian
authors.forename: Olivier
authors.initials: O
authors.lastname: Meilhac
authors.forename: Catherine
authors.initials: C
authors.lastname: Chaussain
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002113:Calcification, Physiologic; D002648:Child; D002675:Child, Preschool; D002762:Cholecalciferol / Q000627:therapeutic use; D003804:Dentin / Q000737:chemistry / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D053098:Familial Hypophosphatemic Rickets / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D040181:Genetic Diseases, X-Linked; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014815:Vitamins / Q000627:therapeutic use
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C486579:MEPE protein, human; D010455:Peptides; D010750:Phosphoproteins; D014815:Vitamins; D002762:Cholecalciferol; D053402:PHEX Phosphate Regulating Neutral Endopeptidase