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*
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*
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DOI：
10.1074/jbc.m404824200
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发表时间：
2004-10
影响因子：
4.8
通讯作者：
Y. Tanimoto;M. Yokozeki;K. Hiura;Kazuya Matsumoto;H. Nakanishi;Toshio Matsumoto;P. Marie;K. Moriyama-K.-M
中科院分区：
文献类型：
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作者：
Y. Tanimoto;M. Yokozeki;K. Hiura;Kazuya Matsumoto;H. Nakanishi;Toshio Matsumoto;P. Marie;K. Moriyama-K.-M
Apert综合征是一种常染色体显性遗传病，以颅缝融合和骨性并指为特征，与成纤维细胞生长因子受体(FGFR)2的点突变(S252W和P253R)相关，导致FGFR2激活。在这里，我们研究了FGFR2 S252W突变在成骨细胞分化中的作用。2例S252W突变的Apert患者指骨来源的成骨细胞与2例独立的非综合征性多指患者来源的对照细胞相比，其碱性磷酸酶活性、骨钙素和骨桥蛋白mRNA的表达以及矿化结节的形成更为显著。稳定表达FGFR2剪接变异体的人骨肉瘤细胞(MG63-AP和MG63-IIIc)(FGFR2IIIcS252W和FGFR2IIIc)的RUNX2mRNA表达水平均高于亲本细胞。此外，MG63-AP的骨桥蛋白mRNA表达水平高于MG63-IIIc。高表达可溶性FGFR2IIIcS252W的COS-1细胞条件培养液可抑制MG63-AP成骨标志物基因表达增强和矿化结节形成。此外，可溶性FGFR2IIIcS252W可阻断FGF2在小鼠颅骨器官培养系统中诱导的成骨反应。这些结果表明，FGFR2基因的S252W突变增强了人成骨细胞的表型，S252W突变的可溶性FGFR2通过对Apert综合征中FGFR2信号的显性负向作用控制了S252W突变诱导的成骨细胞分化。
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.