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.
Highlights
Skeletal dysplasias comprise a diverse group of disorders
In this study we evaluated the efficacy of BMN 111 for the correction of craniosynostosis and the more general craniofacial dysplasia in this mouse model during postnatal development
We first determined whether natriuretic peptide receptor 2 (NPR2) protein is expressed in the coronal suture by immunohistochemistry prior to testing whether BMN 111 could act through NPR2 to ameliorate cranial dysmorphology in Crouzon mice
Summary
The skeleton forms via both intramembranous ossification, by which osteoblasts differentiate directly from mesenchyme to form bone, and endochondral ossification, by which a cartilage template of individual bones is first established and replaced by osteoblasts to form the final bone. The flat bones of the skull form via intramembranous ossification, while the base of the skull, vertebrae, and long. BMN 111 treatment of Crouzon syndrome mice imaging methodology, data curation, visualization, and analysis, which were performed by LZ and RM, who along with LS and TO reviewed and edited the manuscript. Their specific roles are articulated in the ‘Author Contributions’ section. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, which had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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