PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.

<h4>Context</h4>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...

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Autores principales:	Lesya V Zelenchuk, Anne-Marie Hedge, Peter S N Rowe
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/db94a614e0f3454eaed6351fb08f1830
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spelling	oai:doaj.org-article:db94a614e0f3454eaed6351fb08f18302021-11-18T08:18:51ZPHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.1932-620310.1371/journal.pone.0097326https://doaj.org/article/db94a614e0f3454eaed6351fb08f18302014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24839967/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Context</h4>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.<h4>Design</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Lesya V ZelenchukAnne-Marie HedgePeter S N RowePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 5, p e97326 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lesya V Zelenchuk Anne-Marie Hedge Peter S N Rowe PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.
description	<h4>Context</h4>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.<h4>Design</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
format	article
author	Lesya V Zelenchuk Anne-Marie Hedge Peter S N Rowe
author_facet	Lesya V Zelenchuk Anne-Marie Hedge Peter S N Rowe
author_sort	Lesya V Zelenchuk
title	PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.
title_short	PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.
title_full	PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.
title_fullStr	PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.
title_full_unstemmed	PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.
title_sort	phex mimetic (spr4-peptide) corrects and improves hyp and wild type mice energy-metabolism.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/db94a614e0f3454eaed6351fb08f1830
work_keys_str_mv	AT lesyavzelenchuk phexmimeticspr4peptidecorrectsandimproveshypandwildtypemiceenergymetabolism AT annemariehedge phexmimeticspr4peptidecorrectsandimproveshypandwildtypemiceenergymetabolism AT petersnrowe phexmimeticspr4peptidecorrectsandimproveshypandwildtypemiceenergymetabolism
_version_	1718421954656993280

PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism.

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