The primary site of the acrocephalic feature in Apert syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling
The primary site of the acrocephalic feature in Apert syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling
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DOI：
10.1016/j.bone.2010.11.014
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发表时间：
2011-04-01
期刊：
影响因子：
4.1
通讯作者：
Slavkin, Harold C.
中科院分区：
文献类型：
--
作者：
Nagata, Masaki;Nuckolls, Glen H.;Slavkin, Harold C.
颅骨缝中成骨细胞骨锚的激活被认为是突变型FGFR 2相关颅面骨发育不全的基本病理条件。然而，早期临床研究表明，颅底软骨发育异常是Apert综合征（AS）的主要异常特征。为了研究AS中颅底软骨生长的意义，我们建立了一种携带AS型突变体Fgfr 2 IIIc的转基因小鼠（Fgfr 2 IIIc（P253 R）小鼠），该小鼠受Col 2a 1启动子-增强子的控制。尽管成骨细胞缺乏Fgfr 2 IIIc（P253 R）的表达，但软骨细胞分化和生长的完全破坏再现了AS样头畸形，伴有短前颅底，颅底软骨结合融合，上颌发育不全和颅骨缝骨结合，躯干和四肢无明显异常。基因表达分析表明p21，Ihh和Mmp-13的上调伴随着Sox 9和Runx 2表达的适度增加，表明Fgfr 2 IIIc（P253 R）小鼠颅底软骨细胞成熟和肥大的加速。此外，突变型FGFR 2 IIIc（P253 R）受体与FGF 2和FGF 10的获得性亲和力和特异性被认为是颅底中选择性激活FGFR 2信号传导的机制。在本报告中，我们强烈建议AS的尖头特征不仅是冠状缝骨性结合的结果，而且是由于颅底生长的原发性障碍和过早的软骨内骨化的结果。(C)2010年爱思唯尔公司All rights reserved.
Activation of osteoblastic bone anabolism in the calvarial sutures is considered to be the essential pathologic condition underlying mutant FGFR2-related craniofacial dysostosis. However, early clinical investigations indicated that abnormal cartilage development in the cranial base was rather a primary site of abnormal feature in Apert Syndrome (AS). To examine the significance of cartilaginous growth of the cranial base in AS, we generated a transgenic mouse bearing AS-type mutant Fgfr2IIIc under the control of the Col2a1 promoter-enhancer (Fgfr2IIIc(P253R) mouse). Despite the lacking expression of Fgfr2IIIc(P253R) in osteoblasts, exclusive disruption of chondrocytic differentiation and growth reproduced AS-like acrocephaly accompanied by short anterior cranial base with fusion of the cranial base synchondroses, maxillary hypoplasia and synostosis of the calvarial sutures with no significant abnormalities in the trunk and extremities. Gene expression analyses demonstrated upregulation of p21, Ihh and Mmp-13 accompanied by modest increase in expression of Sox9 and Runx2, indicating acceleration of chondrocytic maturation and hypertrophy in the cranial base of the Fgfr2IIIc(P253R) mice. Furthermore, an acquired affinity and specificity of mutant FGFR2IIIc(P253R) receptor with FGF2 and FGF10 is suggested as a mechanism of activation of FGFR2 signaling selectively in the cranial base. In this report, we strongly suggest that the acrocephalic feature of AS is not alone a result of the coronal suture synostosis, but is a result of the primary disturbance in growth of the cranial base with precocious endochondral ossification. (C) 2010 Elsevier Inc. All rights reserved.