Development of new therapeutic strategy for the craniosynostosis patients

本研究旨在阐明Apert综合征小鼠模型颅缝闭锁的病因机制，并验证携带S252W突变的纯化可溶性FGFR2 （sFGFR2IIIcS252W）对Apert综合征小鼠颅骨缝合线的体外作用。我们观察到，在Apert综合征小鼠的冠状缝线中，表皮发育不可或缺的Fgf10、Esrp1和Fgfr2IIIb的表达增加。纯化的sFGFR2IIIcS252W对Fgf2具有结合亲和力，但也与FGFR2IIIc、FGFR2IIIcS252W和fgfr2iiibs252w形成异源二聚体。sFGFR2IIIcS252W与纳米凝胶络合后保持冠状缝的通畅，而不含sFGFR2S252W的纳米凝胶则观察到结膜紧闭。因此，根据我们目前的数据，我们认为Fgf10和Fgfr2IIIb表达的增加可能会诱导Apert综合征患者颅缝闭锁的发作，并且适当地给予纯化的sFGFR2IIIcS252W可能有效治疗这种疾病。

Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for Fgf2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder.