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Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2

OBJECTIVE: The canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na(+...

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Autores principales: Bon, Nina, Frangi, Giulia, Sourice, Sophie, Guicheux, Jérôme, Beck-Cormier, Sarah, Beck, Laurent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001877/
https://www.ncbi.nlm.nih.gov/pubmed/29551636
http://dx.doi.org/10.1016/j.molmet.2018.02.007
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author Bon, Nina
Frangi, Giulia
Sourice, Sophie
Guicheux, Jérôme
Beck-Cormier, Sarah
Beck, Laurent
author_facet Bon, Nina
Frangi, Giulia
Sourice, Sophie
Guicheux, Jérôme
Beck-Cormier, Sarah
Beck, Laurent
author_sort Bon, Nina
collection PubMed
description OBJECTIVE: The canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na(+)-Pi co-transporters PiT1/Slc20a1 and PiT2/Slc20a2 were required for mediating Pi-dependent signaling. Here, we addressed the contribution of PiT1 and PiT2 to the regulation of Fgf23 secretion. METHODS: To this aim, we used PiT2 KO and DMP1Cre; PiT1(lox/lox) fed Pi-modified diets, as well as ex vivo isolated long bone shafts. Fgf23 secretion and expression of Pi homeostasis-related genes were assessed. RESULTS: In vivo, PiT2 KO mice responded inappropriately to low-Pi diets, displaying abnormally normal serum levels of intact Fgf23. Despite the high iFgf23 level, serum Pi levels remained unaffected, an effect that may relate to lower αKlotho expression in the kidney. Moreover, consistent with a role of PiT2 as a possible endocrine Pi sensor, the iFGF23/cFGF23 ratios were suppressed in PiT2 KO mice, irrespective of the Pi loads. While deletion of PiT1 in osteocytes using the DMP1-Cre mice was inefficient, adenovirus-mediated deletion of PiT1 in isolated long bone shafts suggested that PiT1 does not contribute to Pi-dependent regulation of Fgf23 secretion. In contrast, using isolated bone shafts from PiT2 KO mice, we showed that PiT2 was necessary for the appropriate Pi-dependent secretion of Fgf23, independently from possible endocrine regulatory loops. CONCLUSIONS: Our data provide initial mechanistic insights underlying the Pi-dependent regulation of Fgf23 secretion in identifying PiT2 as a potential player in this process, at least in high Pi conditions. Targeting PiT2, therefore, could improve excess FGF23 in hyperphosphatemic conditions such as chronic kidney disease.
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spelling pubmed-60018772018-06-15 Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2 Bon, Nina Frangi, Giulia Sourice, Sophie Guicheux, Jérôme Beck-Cormier, Sarah Beck, Laurent Mol Metab Brief Communication OBJECTIVE: The canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na(+)-Pi co-transporters PiT1/Slc20a1 and PiT2/Slc20a2 were required for mediating Pi-dependent signaling. Here, we addressed the contribution of PiT1 and PiT2 to the regulation of Fgf23 secretion. METHODS: To this aim, we used PiT2 KO and DMP1Cre; PiT1(lox/lox) fed Pi-modified diets, as well as ex vivo isolated long bone shafts. Fgf23 secretion and expression of Pi homeostasis-related genes were assessed. RESULTS: In vivo, PiT2 KO mice responded inappropriately to low-Pi diets, displaying abnormally normal serum levels of intact Fgf23. Despite the high iFgf23 level, serum Pi levels remained unaffected, an effect that may relate to lower αKlotho expression in the kidney. Moreover, consistent with a role of PiT2 as a possible endocrine Pi sensor, the iFGF23/cFGF23 ratios were suppressed in PiT2 KO mice, irrespective of the Pi loads. While deletion of PiT1 in osteocytes using the DMP1-Cre mice was inefficient, adenovirus-mediated deletion of PiT1 in isolated long bone shafts suggested that PiT1 does not contribute to Pi-dependent regulation of Fgf23 secretion. In contrast, using isolated bone shafts from PiT2 KO mice, we showed that PiT2 was necessary for the appropriate Pi-dependent secretion of Fgf23, independently from possible endocrine regulatory loops. CONCLUSIONS: Our data provide initial mechanistic insights underlying the Pi-dependent regulation of Fgf23 secretion in identifying PiT2 as a potential player in this process, at least in high Pi conditions. Targeting PiT2, therefore, could improve excess FGF23 in hyperphosphatemic conditions such as chronic kidney disease. Elsevier 2018-02-26 /pmc/articles/PMC6001877/ /pubmed/29551636 http://dx.doi.org/10.1016/j.molmet.2018.02.007 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Brief Communication
Bon, Nina
Frangi, Giulia
Sourice, Sophie
Guicheux, Jérôme
Beck-Cormier, Sarah
Beck, Laurent
Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2
title Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2
title_full Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2
title_fullStr Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2
title_full_unstemmed Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2
title_short Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2
title_sort phosphate-dependent fgf23 secretion is modulated by pit2/slc20a2
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001877/
https://www.ncbi.nlm.nih.gov/pubmed/29551636
http://dx.doi.org/10.1016/j.molmet.2018.02.007
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