SPR4-peptide alters bone metabolism of normal and HYP mice.
Bone
; 72: 23-33, 2015 Mar.
Article
en En
| MEDLINE
| ID: mdl-25460577
ABSTRACT
CONTEXT ASARM-peptides are substrates and ligands for PHEX, the gene responsible for X-linked hypophosphatemic rickets (HYP). PHEX binds to the DMP1-ASARM-motif to form a trimeric-complex with α5ß3-integrin on the osteocyte surface and this suppresses FGF23 expression. ASARM-peptide disruption of this complex increases FGF23 expression. We used a 4.2kDa peptide (SPR4) that binds to ASARM-peptide and ASARM-motif to study DMP1-PHEX interactions and to assess SPR4 for treating inherited hypophosphatemic rickets. DESIGN:
Subcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle into wild-type mice (WT) and HYP-mice for 4 weeks.RESULTS:
Asymmetrically distributed mineralization defects occurred with WT-SPR4 femurs. Specifically, SPR4 induced negative effects on trabecular bone and increased bone volume and mineralization in cortical-bone. Markedly increased sclerostin and reduced active ß-catenin occurred with HYP mice. SPR4-infusion suppressed sclerostin and increased active ß-catenin in WT and HYP mice and improved HYP-mice trabecular mineralization defects but not cortical mineralization defects.CONCLUSIONS:
SPR4-peptide has bimodal activity and acts by (1) preventing DMP1 binding to PHEX and (2) sequestering an inhibitor of DMP1-PHEX binding, ASARM-peptide. In PHEX defective HYP-mice the second pathway predominates. Although SPR4-peptide improved trabecular calcification defects, decreased sclerostin and increased active ß-catenin it did not correct HYP-mice cortical mineralization defects on a normal phosphate diet. Thus, for inherited hypophosphatemic rickets patients on a normal phosphate diet, SPR4-peptide is not a useful therapeutic.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Péptidos
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Huesos
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Glicoproteínas
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Enfermedades Genéticas Ligadas al Cromosoma X
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Beta Catenina
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Raquitismo Hipofosfatémico Familiar
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2015
Tipo del documento:
Article