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

研究成果: ジャーナルへの寄稿記事

17 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)847-856
ページ数10
ジャーナルBone
48
発行部数4
DOI
出版物ステータス出版済み - 4 1 2011

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Acrocephalosyndactylia
Skull Base
Sutures
Synostosis
Growth
Craniofacial Dysostosis
Craniosynostoses
Fibroblast Growth Factor 2
Osteoblasts
Osteogenesis
Hypertrophy
Transgenic Mice
Cartilage
Up-Regulation
Extremities
Gene Expression
Bone and Bones

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

これを引用

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

:: Bone, 巻 48, 番号 4, 01.04.2011, p. 847-856.

研究成果: ジャーナルへの寄稿記事

Nagata, M, Nuckolls, GH, Wang, X, Shum, L, Seki, Y, Kawase, T, Takahashi, K, Nonaka, K, Takahashi, I, Noman, AA, Suzuki, K & Slavkin, HC 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, 巻. 48, 番号 4, pp. 847-856. https://doi.org/10.1016/j.bone.2010.11.014
Nagata, Masaki ; Nuckolls, Glen H. ; Wang, Xibin ; Shum, Lillian ; Seki, Yukie ; Kawase, Tomoyuki ; Takahashi, Katsu ; Nonaka, Kazuaki ; Takahashi, Ichiro ; Noman, Arhab A. ; Suzuki, Kenji ; Slavkin, Harold C. / 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. 2011 ; 巻 48, 番号 4. pp. 847-856.
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title = "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",
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.",
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T1 - 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

AU - Nagata, Masaki

AU - Nuckolls, Glen H.

AU - Wang, Xibin

AU - Shum, Lillian

AU - Seki, Yukie

AU - Kawase, Tomoyuki

AU - Takahashi, Katsu

AU - Nonaka, Kazuaki

AU - Takahashi, Ichiro

AU - Noman, Arhab A.

AU - Suzuki, Kenji

AU - Slavkin, Harold C.

PY - 2011/4/1

Y1 - 2011/4/1

N2 - 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.

AB - 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.

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