title: MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia.
abstract: Mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X-chromosome) cause X-linked familial hypophosphatemic rickets (XLH), a disorder having severe bone and tooth dentin mineralization defects. The absence of functional PHEX leads to abnormal accumulation of ASARM (acidic serine- and aspartate-rich motif) peptide - a substrate for PHEX and a strong inhibitor of mineralization - derived from MEPE (matrix extracellular phosphoglycoprotein) and other matrix proteins. MEPE-derived ASARM peptide accumulates in tooth dentin of XLH patients where it may impair dentinogenesis. Here, we investigated the effects of ASARM peptides in vitro and in vivo on odontoblast differentiation and matrix mineralization. Dental pulp stem cells from human exfoliated deciduous teeth (SHEDs) were seeded into a 3D collagen scaffold, and induced towards odontogenic differentiation. Cultures were treated with synthetic ASARM peptides (phosphorylated and nonphosphorylated) derived from the human MEPE sequence. Phosphorylated ASARM peptide inhibited SHED differentiation in vitro, with no mineralized nodule formation, decreased odontoblast marker expression, and upregulated MEPE expression. Phosphorylated ASARM peptide implanted in a rat molar pulp injury model impaired reparative dentin formation and mineralization, with increased MEPE immunohistochemical staining. In conclusion, using complementary models to study tooth dentin defects observed in XLH, we demonstrate that the MEPE-derived ASARM peptide inhibits both odontogenic differentiation and matrix mineralization, while increasing MEPE expression. These results contribute to a partial mechanistic explanation of XLH pathogenesis: direct inhibition of mineralization by ASARM peptide leads to the mineralization defects in XLH teeth. This process appears to be positively reinforced by the increased MEPE expression induced by ASARM. The MEPE-ASARM system can therefore be considered as a potential therapeutic target.
authors: EA 2496, Pathologies, Imaging and Biotherapies of the Tooth, UFR Odontologie, University Paris Descartes PRES Sorbonne Paris Cité, Montrouge, France.
authors: Benjamin
authors: B
authors: Salmon
authors: Claire
authors: C
authors: Bardet
authors: Mayssam
authors: M
authors: Khaddam
authors: Jiar
authors: J
authors: Naji
authors: Benjamin R
authors: BR
authors: Coyac
authors: Brigitte
authors: B
authors: Baroukh
authors: Franck
authors: F
authors: Letourneur
authors: Julie
authors: J
authors: Lesieur
authors: Franck
authors: F
authors: Decup
authors: Dominique
authors: D
authors: Le Denmat
authors: Antonino
authors: A
authors: Nicoletti
authors: Anne
authors: A
authors: Poliard
authors: Peter S
authors: PS
authors: Rowe
authors: Eric
authors: E
authors: Huet
authors: Sibylle Opsahl
authors: SO
authors: Vital
authors: Agnès
authors: A
authors: Linglart
authors: Marc D
authors: MD
authors: McKee
authors: Catherine
authors: C
authors: Chaussain
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003782:Dental Pulp / Q000166:cytology*; D053098:Familial Hypophosphatemic Rickets / Q000378:metabolism*; D040181:Genetic Diseases, X-Linked; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009804:Odontoblasts / Q000166:cytology* / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D055815:Young Adult
chemical_list: D010455:Peptides