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Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis.
PLoS One. 2014; 9(7):e101693.Plos

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+Show Affiliations

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.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.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.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.ERATO, Japan Science and Technology Agency, Tokyo, Japan.Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan; Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25003957

Citation

Yokota, Masako, et al. "Therapeutic Effect of Nanogel-based Delivery of Soluble FGFR2 With S252W Mutation On Craniosynostosis." PloS One, vol. 9, no. 7, 2014, pp. e101693.
Yokota M, Kobayashi Y, Morita J, et al. Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis. PLoS ONE. 2014;9(7):e101693.
Yokota, M., Kobayashi, Y., Morita, J., Suzuki, H., Hashimoto, Y., Sasaki, Y., Akiyoshi, K., & Moriyama, K. (2014). Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis. PloS One, 9(7), e101693. https://doi.org/10.1371/journal.pone.0101693
Yokota M, et al. Therapeutic Effect of Nanogel-based Delivery of Soluble FGFR2 With S252W Mutation On Craniosynostosis. PLoS ONE. 2014;9(7):e101693. PubMed PMID: 25003957.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis. AU - Yokota,Masako, AU - Kobayashi,Yukiho, AU - Morita,Jumpei, AU - Suzuki,Hiroyuki, AU - Hashimoto,Yoshihide, AU - Sasaki,Yoshihiro, AU - Akiyoshi,Kazunari, AU - Moriyama,Keiji, Y1 - 2014/07/08/ PY - 2013/11/20/received PY - 2014/06/11/accepted PY - 2014/7/9/entrez PY - 2014/7/9/pubmed PY - 2015/3/31/medline SP - e101693 EP - e101693 JF - PloS one JO - PLoS ONE VL - 9 IS - 7 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/25003957/Therapeutic_effect_of_nanogel_based_delivery_of_soluble_FGFR2_with_S252W_mutation_on_craniosynostosis_ L2 - http://dx.plos.org/10.1371/journal.pone.0101693 DB - PRIME DP - Unbound Medicine ER -