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C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model.
PLoS One. 2018; 13(7):e0201492.Plos

Abstract

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 Fgfr3Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2cC342Y/+ 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 Fgfr2cC342Y/+ 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.

Authors+Show Affiliations

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.BioMarin Pharmaceutical, Novato, California, United States of America.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.BioMarin Pharmaceutical, Novato, California, United States of America.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.BioMarin Pharmaceutical, Novato, California, United States of America.BioMarin Pharmaceutical, Novato, California, United States of America.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30048539

Citation

Holmes, Greg, et al. "C-type Natriuretic Peptide Analog Treatment of Craniosynostosis in a Crouzon Syndrome Mouse Model." PloS One, vol. 13, no. 7, 2018, pp. e0201492.
Holmes G, Zhang L, Rivera J, et al. C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. PLoS ONE. 2018;13(7):e0201492.
Holmes, G., Zhang, L., Rivera, J., Murphy, R., Assouline, C., Sullivan, L., Oppeneer, T., & Jabs, E. W. (2018). C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. PloS One, 13(7), e0201492. https://doi.org/10.1371/journal.pone.0201492
Holmes G, et al. C-type Natriuretic Peptide Analog Treatment of Craniosynostosis in a Crouzon Syndrome Mouse Model. PLoS ONE. 2018;13(7):e0201492. PubMed PMID: 30048539.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. AU - Holmes,Greg, AU - Zhang,Lening, AU - Rivera,Joshua, AU - Murphy,Ryan, AU - Assouline,Claudia, AU - Sullivan,Lorraine, AU - Oppeneer,Todd, AU - Jabs,Ethylin Wang, Y1 - 2018/07/26/ PY - 2018/04/26/received PY - 2018/07/16/accepted PY - 2018/7/27/entrez PY - 2018/7/27/pubmed PY - 2019/1/29/medline SP - e0201492 EP - e0201492 JF - PloS one JO - PLoS ONE VL - 13 IS - 7 N2 - 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 Fgfr3Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2cC342Y/+ 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 Fgfr2cC342Y/+ 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/30048539/C_type_natriuretic_peptide_analog_treatment_of_craniosynostosis_in_a_Crouzon_syndrome_mouse_model_ L2 - http://dx.plos.org/10.1371/journal.pone.0201492 DB - PRIME DP - Unbound Medicine ER -