Abstract

Craniosynostosis (CS), the premature and pathological fusion of cranial sutures, is a relatively common developmental disorder. Elucidation of the pathways involved and thus therapeutically targeting it would be promising for the prevention of CS. In the present study, we examined the role of BMP pathway in the all-trans retinoic acid (atRA)–induced CS model and tried to target the pathway in vivo via PLGA-based control release. As expected, the posterior frontal suture was found to fuse prematurely in the atRA subcutaneous injection mouse model. Further mechanism study revealed that atRA could repress the proliferation while promote the osteogenic differentiation of suture-derived mesenchymal cells (SMCs). Moreover, BMP signal pathway was found to be activated by atRA, as seen from increased expression of BMPR-2 and pSMAD1/5/9. Recombinant mouse Noggin blocked the atRA-induced enhancement of osteogenesis of SMCs in vitro. In vivo, PLGA microsphere encapsulated with Noggin significantly prevented the atRA-induced suture fusion. Collectively, these data support the hypothesis that BMP signaling is involved in retinoic acid–induced premature fusion of cranial sutures, while PLGA microsphere–based control release of Noggin emerges as a promising strategy for prevention of atRA-induced suture fusion.

Highlights

  • Craniosynostosis (CS), the premature fusion of one or more of the cranial sutures, which causes secondary deformations of the cranial vault, cranial base, and brain, occurs with an estimated birth prevalence of 1 in 2000 to 2500 live births worldwide (Johnson and Wilkie 2011; Wilkie et al 2010)

  • We for the first time revealed that excessive bone morphogenetic protein (BMP) signal pathway is essential for all-trans retinoic acid (atRA)-induced CS

  • We revealed that PLGA microsphere encapsulated with Noggin, an inhibitor of BMP pathway, significantly prevented and partially restored the atRA-induced suture fusion in vivo

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Summary

Introduction

Craniosynostosis (CS), the premature fusion of one or more of the cranial sutures, which causes secondary deformations of the cranial vault, cranial base, and brain, occurs with an estimated birth prevalence of 1 in 2000 to 2500 live births worldwide (Johnson and Wilkie 2011; Wilkie et al 2010). Craniosynostosis can lead to dramatic clinical manifestations in terms of cosmesis and functional impairment including craniofacial deformation, mental retardation, and difficulties with vision, hearing, and breathing (Wilkie and Morriss-Kay 2001). Despite the recent progress in molecular biology and using animal models, many details of the suture biology and the pathophysiological mechanisms of craniosynostosis remain unknown

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