title: Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis.
abstract: Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are frequently required to reduce morphological and functional defects in patients with Apert syndrome; therefore, the development of noninvasive procedures to treat Apert syndrome is critical. 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 fibroblast growth factor (Fgf) 2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. Administration of sFGFR2IIIcS252W also inhibited Fgf2-dependent proliferation, phosphorylation of intracellular signaling molecules, and mineralization of FGFR2S252W-overexpressing MC3T3-E1 osteoblasts. 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.
authors.affiliation: Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Yokota
authors.affiliation: Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yukiho
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Morita
authors.affiliation: Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: ERATO, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan; Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan; Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; ERATO, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.affiliation: Maxillofacial Orthognathics, Department of Maxillofacial Reconstruction and Function, Division of Maxillofacial/Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Moriyama
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D019943:Amino Acid Substitution; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003062:Codon; D003393:Cranial Sutures / Q000002:abnormalities; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015870:Gene Expression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000080385:Nanogels; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011094:Polyethyleneimine / Q000008:administration & dosage*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism
chemical_list: D003062:Codon; C000588453:ESRP1 protein, mouse; D051526:Fibroblast Growth Factor 10; D000080385:Nanogels; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C413692:polyethylene glycol polyethyleneimine nanogel; D016222:Fibroblast Growth Factor 2; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D051497:Receptor, Fibroblast Growth Factor, Type 2