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

Masaki Nagata, Glen H. Nuckolls, Xibin Wang, Lillian Shum, Yukie Seki, Tomoyuki Kawase, Katsu Takahashi, Kazuaki Nonaka, Ichiro Takahashi, Arhab A. Noman, Kenji Suzuki, Harold C. Slavkin

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Abstract

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 (Fgfr2IIIcP253R mouse). Despite the lacking expression of Fgfr2IIIcP253R 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 Fgfr2IIIcP253R mice. Furthermore, an acquired affinity and specificity of mutant FGFR2IIIcP253R 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.

Original languageEnglish
Pages (from-to)847-856
Number of pages10
JournalBone
Volume48
Issue number4
DOIs
Publication statusPublished - Apr 1 2011

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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    Nagata, M., Nuckolls, G. H., Wang, X., Shum, L., Seki, Y., Kawase, T., Takahashi, K., Nonaka, K., Takahashi, I., Noman, A. A., Suzuki, K., & Slavkin, H. C. (2011). 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. Bone, 48(4), 847-856. https://doi.org/10.1016/j.bone.2010.11.014