Lomri A, Lemonnier J, Hott M, de Parseval N, Lajeunie E, Munnich A, Renier D, Marie P J
INSERM U 349, Cell and Molecular Biology of Bone and Cartilage, Lariboisière Hospital, 75475 Paris Cedex 10, France.
J Clin Invest. 1998 Mar 15;101(6):1310-7.
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.
Apert综合征与成纤维细胞生长因子受体（FGFR）2突变相关，其特征为颅缝过早融合。我们分析了来自患有FGFR - 2突变的Apert综合征婴儿和胎儿的颅骨细胞的增殖和分化情况。组织学分析显示，与年龄匹配的对照组相比，Apert综合征胎儿颅骨存在过早骨化、骨膜下骨形成范围增加以及碱性磷酸酶阳性的前成骨细胞。从Apert综合征婴儿和胎儿分离出的前成骨细胞在基础条件下或对外源性FGF - 2反应时显示出正常的细胞生长。相比之下，在具有最常见的Apert综合征FGFR - 2突变（Ser252Trp）的突变胎儿颅骨细胞中，碱性磷酸酶阳性的颅骨细胞数量比正常情况高四倍，这表明成骨细胞谱系中的细胞成熟速率增加。生化和Northern印迹分析还表明，在突变胎儿颅骨细胞中，碱性磷酸酶和1型胶原蛋白的表达比正常情况高2 - 10倍。与对照永生化胎儿颅骨细胞相比，在聚集体中培养的永生化突变胎儿颅骨细胞形成的矿化基质的体外产量也显著增加。结果表明，Apert综合征FGFR - 2突变导致进入成骨途径的前体细胞数量增加，最终导致胎儿发育过程中骨膜下骨基质形成增加和颅骨过早骨化，这在Apert综合征性颅缝早闭的基因型改变和细胞表型之间建立了联系。
