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A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome.
J Biol Chem. 2004 Oct 29; 279(44):45926-34.JB

Abstract

Apert syndrome is an autosomal dominant disease characterized by craniosynostosis and bony syndactyly associated with point mutations (S252W and P253R) in the fibroblast growth factor receptor (FGFR) 2 that cause FGFR2 activation. Here we investigated the role of the S252W mutation of FGFR2 on osteoblastic differentiation. Osteoblastic cells derived from digital bone in two Apert patients with the S252W mutation showed more prominent alkaline phosphatase activity, osteocalcin and osteopontin mRNA expression, and mineralized nodule formation compared with the control osteoblastic cells derived from two independent non-syndromic polydactyly patients. Stable clones of the human MG63 osteosarcoma cells (MG63-Ap and MG63-IIIc) overexpressing a splice variant form of FGFR2 with or without the S252W mutation (FGFR2IIIcS252W and FGFR2IIIc) showed a higher RUNX2 mRNA expression than parental MG63 cells. Furthermore MG63-Ap exhibited a higher osteopontin mRNA expression than did MG63-IIIc. The enhanced osteoblastic marker gene expression and mineralized nodule formation of the MG63-Ap was inhibited by the conditioned medium from the COS-1 cells overexpressing the soluble FGFR2IIIcS252W. Furthermore the FGF2-induced osteogenic response in the mouse calvarial organ culture system was blocked by the soluble FGFR2IIIcS252W. These results show that the S252W mutation in the FGFR2 gene enhances the osteoblast phenotype in human osteoblasts and that a soluble FGFR2 with the S252W mutation controls osteoblast differentiation induced by the S252W mutation through a dominant negative effect on FGFR2 signaling in Apert syndrome.

Authors+Show Affiliations

Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15310757

Citation

Tanimoto, Yukiho, et al. "A Soluble Form of Fibroblast Growth Factor Receptor 2 (FGFR2) With S252W Mutation Acts as an Efficient Inhibitor for the Enhanced Osteoblastic Differentiation Caused By FGFR2 Activation in Apert Syndrome." The Journal of Biological Chemistry, vol. 279, no. 44, 2004, pp. 45926-34.
Tanimoto Y, Yokozeki M, Hiura K, et al. A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome. J Biol Chem. 2004;279(44):45926-34.
Tanimoto, Y., Yokozeki, M., Hiura, K., Matsumoto, K., Nakanishi, H., Matsumoto, T., Marie, P. J., & Moriyama, K. (2004). A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome. The Journal of Biological Chemistry, 279(44), 45926-34.
Tanimoto Y, et al. A Soluble Form of Fibroblast Growth Factor Receptor 2 (FGFR2) With S252W Mutation Acts as an Efficient Inhibitor for the Enhanced Osteoblastic Differentiation Caused By FGFR2 Activation in Apert Syndrome. J Biol Chem. 2004 Oct 29;279(44):45926-34. PubMed PMID: 15310757.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome. AU - Tanimoto,Yukiho, AU - Yokozeki,Masahiko, AU - Hiura,Kenji, AU - Matsumoto,Kazuya, AU - Nakanishi,Hideki, AU - Matsumoto,Toshio, AU - Marie,Pierre J, AU - Moriyama,Keiji, Y1 - 2004/08/13/ PY - 2004/8/18/pubmed PY - 2004/12/16/medline PY - 2004/8/18/entrez SP - 45926 EP - 34 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 279 IS - 44 N2 - Apert syndrome is an autosomal dominant disease characterized by craniosynostosis and bony syndactyly associated with point mutations (S252W and P253R) in the fibroblast growth factor receptor (FGFR) 2 that cause FGFR2 activation. Here we investigated the role of the S252W mutation of FGFR2 on osteoblastic differentiation. Osteoblastic cells derived from digital bone in two Apert patients with the S252W mutation showed more prominent alkaline phosphatase activity, osteocalcin and osteopontin mRNA expression, and mineralized nodule formation compared with the control osteoblastic cells derived from two independent non-syndromic polydactyly patients. Stable clones of the human MG63 osteosarcoma cells (MG63-Ap and MG63-IIIc) overexpressing a splice variant form of FGFR2 with or without the S252W mutation (FGFR2IIIcS252W and FGFR2IIIc) showed a higher RUNX2 mRNA expression than parental MG63 cells. Furthermore MG63-Ap exhibited a higher osteopontin mRNA expression than did MG63-IIIc. The enhanced osteoblastic marker gene expression and mineralized nodule formation of the MG63-Ap was inhibited by the conditioned medium from the COS-1 cells overexpressing the soluble FGFR2IIIcS252W. Furthermore the FGF2-induced osteogenic response in the mouse calvarial organ culture system was blocked by the soluble FGFR2IIIcS252W. These results show that the S252W mutation in the FGFR2 gene enhances the osteoblast phenotype in human osteoblasts and that a soluble FGFR2 with the S252W mutation controls osteoblast differentiation induced by the S252W mutation through a dominant negative effect on FGFR2 signaling in Apert syndrome. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15310757/A_soluble_form_of_fibroblast_growth_factor_receptor_2__FGFR2__with_S252W_mutation_acts_as_an_efficient_inhibitor_for_the_enhanced_osteoblastic_differentiation_caused_by_FGFR2_activation_in_Apert_syndrome_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15310757 DB - PRIME DP - Unbound Medicine ER -