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PIN1 Attenuation Improves Midface Hypoplasia in a Mouse Model of Apert Syndrome

Cited 10 time in Web of Science Cited 11 time in Scopus
Authors

Kim, B.; Shin, H.; Kim, W.; Kim, H.; Cho, Y.; Yoon, H.; Baek, J.; Woo, K.; Lee, Y.; Ryoo, H.

Issue Date
2020-02
Publisher
SAGE Publications
Citation
Journal of Dental Research, Vol.99 No.2, pp.223-232
Abstract
Premature fusion of the cranial suture and midface hypoplasia are common features of syndromic craniosynostosis caused by mutations in the FGFR2 gene. The only treatment for this condition involves a series of risky surgical procedures designed to correct defects in the craniofacial bones, which must be performed until brain growth has been completed. Several pharmacologic interventions directed at FGFR2 downstream signaling have been tested as potential treatments for premature coronal suture fusion in a mouse model of Apert syndrome. However, there are no published studies that have targeted for the pharmacologic treatment of midface hypoplasia. We used Fgfr2(S252W/+) knock-in mice as a model of Apert syndrome and morphometric analyses to identify causal hypoplastic sites in the midface region. Three-dimensional geometric and linear analyses of Fgfr2(S252W/+) mice at postnatal day 0 demonstrated distinct morphologic variance. The premature fusion of anterior facial bones, such as the maxilla, nasal, and frontal bones, rather than the cranium or cranial base, is the main contributing factor toward the anterior-posterior skull length shortening. The cranial base of the mouse model had a noticeable downward slant around the intersphenoid synchondrosis, which is related to distortion of the airway. Within a skull, the facial shape variance was highly correlated with the cranial base angle change along Fgfr2 S252W mutation-induced craniofacial anomalies. The inhibition of an FGFR2 downstream signaling enzyme, PIN1, via genetic knockdown or use of a PIN1 inhibitor, juglone, attenuated the aforementioned deformities in a mouse model of Apert syndrome. Overall, these results indicate that FGFR2 signaling is a key contributor toward abnormal anterior-posterior dimensional growth in the midface region. Our study suggests a novel therapeutic option for the prevention of craniofacial malformations induced by mutations in the FGFR2 gene.
ISSN
0022-0345
URI
https://hdl.handle.net/10371/200502
DOI
https://doi.org/10.1177/0022034519893656
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Cho, Young-Dan조영단
(기금)조교수
  • School of Dentistry
  • Department of Dentistry
Research Area Alveolar bone regeneration, Dental implant surface modification, Periomics

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