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C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model

Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic...

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Autores principales: Holmes, Greg, Zhang, Lening, Rivera, Joshua, Murphy, Ryan, Assouline, Claudia, Sullivan, Lorraine, Oppeneer, Todd, Jabs, Ethylin Wang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062116/
https://www.ncbi.nlm.nih.gov/pubmed/30048539
http://dx.doi.org/10.1371/journal.pone.0201492
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author Holmes, Greg
Zhang, Lening
Rivera, Joshua
Murphy, Ryan
Assouline, Claudia
Sullivan, Lorraine
Oppeneer, Todd
Jabs, Ethylin Wang
author_facet Holmes, Greg
Zhang, Lening
Rivera, Joshua
Murphy, Ryan
Assouline, Claudia
Sullivan, Lorraine
Oppeneer, Todd
Jabs, Ethylin Wang
author_sort Holmes, Greg
collection PubMed
description Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3(Y367C/+) thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2c(C342Y/+) Crouzon syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2c(C342Y/+) and Fgfr2c(+/+) (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation.
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spelling pubmed-60621162018-08-03 C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model Holmes, Greg Zhang, Lening Rivera, Joshua Murphy, Ryan Assouline, Claudia Sullivan, Lorraine Oppeneer, Todd Jabs, Ethylin Wang PLoS One Research Article Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3(Y367C/+) thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2c(C342Y/+) Crouzon syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2c(C342Y/+) and Fgfr2c(+/+) (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation. Public Library of Science 2018-07-26 /pmc/articles/PMC6062116/ /pubmed/30048539 http://dx.doi.org/10.1371/journal.pone.0201492 Text en © 2018 Holmes et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Holmes, Greg
Zhang, Lening
Rivera, Joshua
Murphy, Ryan
Assouline, Claudia
Sullivan, Lorraine
Oppeneer, Todd
Jabs, Ethylin Wang
C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model
title C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model
title_full C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model
title_fullStr C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model
title_full_unstemmed C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model
title_short C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model
title_sort c-type natriuretic peptide analog treatment of craniosynostosis in a crouzon syndrome mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062116/
https://www.ncbi.nlm.nih.gov/pubmed/30048539
http://dx.doi.org/10.1371/journal.pone.0201492
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