PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.
BACKGROUND
PHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders.


METHODS
Subcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks.


RESULTS
SPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice.


CONCLUSIONS
ASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-α5β3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes.
Internal Medicine, The Kidney Institute, Kansas University Medical Center (KUMC), Kansas City, Kansas, United States of America.
Lesya V
LV
Zelenchuk
Internal Medicine, The Kidney Institute, Kansas University Medical Center (KUMC), Kansas City, Kansas, United States of America.
Anne-Marie
AM
Hedge
Internal Medicine, The Kidney Institute, Kansas University Medical Center (KUMC), Kansas City, Kansas, United States of America.
Peter S N
PS
Rowe
D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D053098:Familial Hypophosphatemic Rickets / Q000188:drug therapy* / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*
C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717428:Fgf23 protein, mouse; D010455:Peptides; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase