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MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia.
PLoS One. 2013; 8(2):e56749.Plos

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+Show Affiliations

EA 2496, Pathologies, Imaging and Biotherapies of the Tooth, UFR Odontologie, University Paris Descartes PRES Sorbonne Paris Cité, Montrouge, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23451077

Citation

Salmon, Benjamin, et al. "MEPE-derived ASARM Peptide Inhibits Odontogenic Differentiation of Dental Pulp Stem Cells and Impairs Mineralization in Tooth Models of X-linked Hypophosphatemia." PloS One, vol. 8, no. 2, 2013, pp. e56749.
Salmon B, Bardet C, Khaddam M, et al. MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia. PLoS ONE. 2013;8(2):e56749.
Salmon, B., Bardet, C., Khaddam, M., Naji, J., Coyac, B. R., Baroukh, B., Letourneur, F., Lesieur, J., Decup, F., Le Denmat, D., Nicoletti, A., Poliard, A., Rowe, P. S., Huet, E., Vital, S. O., Linglart, A., McKee, M. D., & Chaussain, C. (2013). MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia. PloS One, 8(2), e56749. https://doi.org/10.1371/journal.pone.0056749
Salmon B, et al. MEPE-derived ASARM Peptide Inhibits Odontogenic Differentiation of Dental Pulp Stem Cells and Impairs Mineralization in Tooth Models of X-linked Hypophosphatemia. PLoS ONE. 2013;8(2):e56749. PubMed PMID: 23451077.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia. AU - Salmon,Benjamin, AU - Bardet,Claire, AU - Khaddam,Mayssam, AU - Naji,Jiar, AU - Coyac,Benjamin R, AU - Baroukh,Brigitte, AU - Letourneur,Franck, AU - Lesieur,Julie, AU - Decup,Franck, AU - Le Denmat,Dominique, AU - Nicoletti,Antonino, AU - Poliard,Anne, AU - Rowe,Peter S, AU - Huet,Eric, AU - Vital,Sibylle Opsahl, AU - Linglart,Agnès, AU - McKee,Marc D, AU - Chaussain,Catherine, Y1 - 2013/02/22/ PY - 2012/11/08/received PY - 2013/01/13/accepted PY - 2013/3/2/entrez PY - 2013/3/2/pubmed PY - 2013/9/4/medline SP - e56749 EP - e56749 JF - PloS one JO - PLoS ONE VL - 8 IS - 2 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23451077/MEPE_derived_ASARM_peptide_inhibits_odontogenic_differentiation_of_dental_pulp_stem_cells_and_impairs_mineralization_in_tooth_models_of_X_linked_hypophosphatemia_ L2 - http://dx.plos.org/10.1371/journal.pone.0056749 DB - PRIME DP - Unbound Medicine ER -