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SPR4-peptide alters bone metabolism of normal and HYP mice.
Bone. 2015 Mar; 72:23-33.BONE

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 α5β3-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 β-catenin occurred with HYP mice. SPR4-infusion suppressed sclerostin and increased active β-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 β-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.

Authors+Show Affiliations

The Kidney Institute, Kansas University Medical Center, Kansas City, KS, USA.The Kidney Institute, Kansas University Medical Center, Kansas City, KS, USA.The Kidney Institute, Kansas University Medical Center, Kansas City, KS, USA. Electronic address: prowe@kumc.edu.

Pub Type(s)

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

Language

eng

PubMed ID

25460577

Citation

Zelenchuk, Lesya V., et al. "SPR4-peptide Alters Bone Metabolism of Normal and HYP Mice." Bone, vol. 72, 2015, pp. 23-33.
Zelenchuk LV, Hedge AM, Rowe PS. SPR4-peptide alters bone metabolism of normal and HYP mice. Bone. 2015;72:23-33.
Zelenchuk, L. V., Hedge, A. M., & Rowe, P. S. (2015). SPR4-peptide alters bone metabolism of normal and HYP mice. Bone, 72, 23-33. https://doi.org/10.1016/j.bone.2014.11.011
Zelenchuk LV, Hedge AM, Rowe PS. SPR4-peptide Alters Bone Metabolism of Normal and HYP Mice. Bone. 2015;72:23-33. PubMed PMID: 25460577.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SPR4-peptide alters bone metabolism of normal and HYP mice. AU - Zelenchuk,Lesya V, AU - Hedge,Anne-Marie, AU - Rowe,Peter S N, Y1 - 2014/11/22/ PY - 2014/08/20/received PY - 2014/11/06/revised PY - 2014/11/14/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2015/10/1/medline KW - DMP1 KW - FGF23 KW - MEPE KW - PHEX KW - Rickets KW - Sclerostin SP - 23 EP - 33 JF - Bone JO - Bone VL - 72 N2 - 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 α5β3-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 β-catenin occurred with HYP mice. SPR4-infusion suppressed sclerostin and increased active β-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 β-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. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/25460577/SPR4_peptide_alters_bone_metabolism_of_normal_and_HYP_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(14)00419-0 DB - PRIME DP - Unbound Medicine ER -