Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome.
Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome.
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发表时间：
1998
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通讯作者：
A. Lomri;J. Lemonnier;M. Hott;N. de Parseval;E. Lajeunie;A. Munnich;D. Rénier;P. Marie
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作者：
A. Lomri;J. Lemonnier;M. Hott;N. de Parseval;E. Lajeunie;A. Munnich;D. Rénier;P. Marie
Apert综合征与成纤维细胞生长因子受体(FGFR)2突变相关，以颅缝过早融合为特征。我们分析了来自Apert婴儿和FGFR-2突变胎儿的颅骨细胞的增殖和分化。组织学分析显示，与年龄匹配的对照组相比，Apert胎颅骨过早骨化，骨膜下骨形成程度增加，碱性磷酸酶阳性的前成骨细胞。从Apert婴儿和胎儿分离的成骨细胞前颅骨细胞在基础条件下或对外源成纤维细胞生长因子-2的反应中显示出正常的细胞生长。相比之下，在Apert FGFR-2突变频率最高(Ser252Trp)的突变胎儿头盖骨细胞中，碱性磷酸酶阳性的头盖骨细胞数量是正常的四倍，这表明成骨细胞谱系中的细胞成熟率增加。生化和Northern印迹分析还表明，突变的胎儿头盖骨细胞碱性磷酸酶和1型胶原的表达比正常高2-10倍。聚集体培养的永生化突变胎颅骨细胞在体外形成矿化基质的能力也明显高于对照永生化胎颅骨细胞。结果表明，Apert FGFR-2突变导致进入成骨途径的前体细胞数量增加，最终导致骨膜下骨基质形成增加和胎儿发育过程中颅骨过早成骨，这建立了Apert综合征颅骨融合症的基因突变与细胞表型之间的联系。
Apert syndrome, associated with fibroblast growth factor receptor (FGFR) 2 mutations, is characterized by premature fusion of cranial sutures. We analyzed proliferation and differentiation of calvaria cells derived from Apert infants and fetuses with FGFR-2 mutations. Histological analysis revealed premature ossification, increased extent of subperiosteal bone formation, and alkaline phosphatase- positive preosteoblastic cells in Apert fetal calvaria compared with age-matched controls. Preosteoblastic calvaria cells isolated from Apert infants and fetuses showed normal cell growth in basal conditions or in response to exogenous FGF-2. In contrast, the number of alkaline phosphatase- positive calvaria cells was fourfold higher than normal in mutant fetal calvaria cells with the most frequent Apert FGFR-2 mutation (Ser252Trp), suggesting increased maturation rate of cells in the osteoblastic lineage. Biochemical and Northern blot analyses also showed that the expression of alkaline phosphatase and type 1 collagen were 2-10-fold greater than normal in mutant fetal calvaria cells. The in vitro production of mineralized matrix formed by immortalized mutant fetal calvaria cells cultured in aggregates was also increased markedly compared with control immortalized fetal calvaria cells. The results show that Apert FGFR-2 mutations lead to an increase in the number of precursor cells that enter the osteogenic pathway, leading ultimately to increased subperiosteal bone matrix formation and premature calvaria ossification during fetal development, which establishes a connection between the altered genotype and cellular phenotype in Apert syndromic craniosynostosis.