Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis

• Published in: PloS one Vol. 9; no. 7; p. e101693
• Main Authors: Yokota, Masako, Kobayashi, Yukiho, Morita, Jumpei, Suzuki, Hiroyuki, Hashimoto, Yoshihide, Sasaki, Yoshihiro, Akiyoshi, Kazunari, Moriyama, Keiji
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.07.2014; Public Library of Science (PLoS)
• Subjects: Acrocephalosyndactylia - genetics; Acrocephalosyndactylia - metabolism; Acrocephalosyndactylia - therapy; Amino Acid Substitution; Analysis; Animal models; Animals; Apert's syndrome; Apoptosis; Biocompatibility; Biology and life sciences; Biomedical materials; Calcification, Physiologic - drug effects; Cell Differentiation - drug effects; Cell Line; Codon; Cranial sutures; Cranial Sutures - abnormalities; Craniosynostosis; Disease Models, Animal; Drug Delivery Systems; Dysostosis; Engineering schools; Etiology; Female; Fibroblast growth factor 10; Fibroblast Growth Factor 10 - genetics; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; Fibroblast growth factor receptor 2; Fibroblast growth factors; Fibroblasts; Gene Expression; Genetic aspects; Genomes; Growth factors; Health aspects; Intracellular signalling; Kinases; Ligands; Male; Medicine and Health Sciences; Mice; Mice, Transgenic; Mineralization; Missense mutation; Mutation; Osteoblasts; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Patients; Phenotype; Phosphorylation; Polyethylene Glycols - administration & dosage; Polyethyleneimine - administration & dosage; Polymer chemistry; Polymers; Protein Binding; Proteins; Receptor, Fibroblast Growth Factor, Type 2 - administration & dosage; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Recombinant Proteins - administration & dosage; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA-Binding Proteins - genetics; Rodents; Surgery; Sutures; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101693

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.