title: SPR4-peptide alters bone metabolism of normal and HYP mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.affiliation: The Kidney Institute, Kansas University Medical Center, Kansas City, KS, USA.
authors.forename: Lesya V
authors.initials: LV
authors.lastname: Zelenchuk
authors.affiliation: The Kidney Institute, Kansas University Medical Center, Kansas City, KS, USA.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Hedge
authors.affiliation: The Kidney Institute, Kansas University Medical Center, Kansas City, KS, USA. Electronic address: prowe@kumc.edu.
authors.forename: Peter S N
authors.initials: PS
authors.lastname: Rowe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D004032:Diet; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics / Q000503:physiopathology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000503:physiopathology*; D006023:Glycoproteins / Q000378:metabolism*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D055114:X-Ray Microtomography; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495267:CTNNB1 protein, mouse; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D010710:Phosphates; D012333:RNA, Messenger; C486030:Sost protein, mouse; D051176:beta Catenin; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse
keywords: DMP1; FGF23; MEPE; PHEX; Rickets; Sclerostin