The Impact of Genes and the Environment on Calvarial Bone Repair and Remodeling in a Murine Model of Craniosynostosis

Abstract

INTRODUCTION: TWIST1 mutation leads to Seathre-Chotzen syndrome involving coronal craniosynostosis. Recent studies have shown that exposure to a selective serotonin reuptake inhibitor, citalopram, can cause craniosynostosis. The purpose of this study is to investigate the genetic and environmental mechanisms underlying aberrant bone repair in a murine model of craniosynostosis. METHODS: Thirteen Twist1+/– mutant mice and wild-type (WT) mice with or without in utero citalopram exposure were generated (n = 5 per group): WT, Twist1+/–, WT + citalopram (n = 5), and Twist1+/– + citalopram. Mice underwent calvarial defect surgery followed by microCT imaging at 1, 2, 3, and 4 weeks postoperatively, at which point they were sacrificed for histological analysis. RESULTS: All mice were fully ambulatory after surgery, with no perioperative complications. MicroCT analysis demonstrated that all Twist1+/– mice exposed to citalopram had craniosynostosis and exhibited excessive and disorganized bone growth after injury. Some Twist1+/– mice without citalopram treatment also developed craniosynostosis and exhibited a similar excessive bone growth pattern; Twist1+/– mice without suture fusion had bone repair similar to that of WT mice. WT defects remained incompletely healed at 4-weeks postoperatively. In contrast, the Twist1+/– mice with citalopram exposure demonstrated full bone fill of the defect at 4-weeks. Twist1+/– mice without citalopram demonstrated more bone fill than WT, but the defect was not entirely filled. CONCLUSION: These preliminary findings after calvarial defect surgeries improve our understanding of bone repair in craniosynostosis. By investigating the mechanisms of bone dynamics in craniosynostosis, we can better understand and prevent the factors implicated in resynostosis after surgery.