SPR4-peptide alters bone metabolism of normal and HYP mice

•We examine in vivo bone effects of SPR4-peptide; a ligand for both PHEX substrate and ligand (ASARM-motif and ASARM-peptide).•SPR4-peptide suppressed sclerostin and increased active β-catenin in wild type (WT) and HYP mice.•SPR4-peptide increased cortical-bone-volume and mineralization but inhibited WT trabecular bone.•SPR4-peptide improved HYP-mice trabecular but not cortical mineralization defects.•On a normal phosphate diet SPR4-peptide is not a useful adjuvant for treating X-linked rickets.

ContextASARM-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 4.2 kDa peptide (SPR4) that binds to ASARM-peptide and ASARM-motif to study DMP1–PHEX interactions and to assess SPR4 for treating inherited hypophosphatemic rickets.DesignSubcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle into wild-type mice (WT) and HYP-mice for 4 weeks.ResultsAsymmetrically 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.ConclusionsSPR4-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.