Abstract
Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS), one of the most common congenital craniofacial deformities. Here we describe the creation and analysis of transgenic mice overexpressing Nell-1. Nell-1 transgenic animals exhibited CS-like phenotypes that ranged from simple to compound synostoses. Histologically, the osteogenic fronts of abnormally closing/closed sutures in these animals revealed calvarial overgrowth and overlap along with increased osteoblast differentiation and reduced cell proliferation. Furthermore, anomalies were restricted to calvarial bone, despite generalized, non-tissue-specific overexpression of Nell-1. In vitro, Nell-1 overexpression accelerated calvarial osteoblast differentiation and mineralization under normal culture conditions. Moreover, Nell-1 overexpression in osteoblasts was sufficient to promote alkaline phosphatase expression and micronodule formation. Conversely, downregulation of Nell-1 inhibited osteoblast differentiation in vitro. In summary, Nell-1 overexpression induced calvarial overgrowth resulting in premature suture closure in a rodent model. Nell-1, therefore, has a novel role in CS development, perhaps as part of a complex chain of events resulting in premature suture closure. On a cellular level, Nell-1 expression may modulate and be both sufficient and required for osteoblast differentiation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 861-870 |
| Number of pages | 10 |
| Journal | Journal of Clinical Investigation |
| Volume | 110 |
| Issue number | 6 |
| DOIs | |
| State | Published - Sep 2002 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
Craniosynostosis in transgenic mice overexpressing Nell-1. / Zhang, Xinli; Kuroda, Shun'ichi; Carpenter, Dale; Nishimura, Ichiro; Soo, Chia; Moats, Rex; Iida, Keisuke; Wisner, Erik R; Hu, Fei Ya; Miao, Steve; Beanes, Steve; Dang, Catherine; Vastardis, Heleni; Longaker, Michael; Tanizawa, Katsuyuki; Kanayama, Norihiro; Saito, Naoaki; Ting, Kang.
In: Journal of Clinical Investigation, Vol. 110, No. 6, 09.2002, p. 861-870.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Craniosynostosis in transgenic mice overexpressing Nell-1
AU - Zhang, Xinli
AU - Kuroda, Shun'ichi
AU - Carpenter, Dale
AU - Nishimura, Ichiro
AU - Soo, Chia
AU - Moats, Rex
AU - Iida, Keisuke
AU - Wisner, Erik R
AU - Hu, Fei Ya
AU - Miao, Steve
AU - Beanes, Steve
AU - Dang, Catherine
AU - Vastardis, Heleni
AU - Longaker, Michael
AU - Tanizawa, Katsuyuki
AU - Kanayama, Norihiro
AU - Saito, Naoaki
AU - Ting, Kang
PY - 2002/9
Y1 - 2002/9
N2 - Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS), one of the most common congenital craniofacial deformities. Here we describe the creation and analysis of transgenic mice overexpressing Nell-1. Nell-1 transgenic animals exhibited CS-like phenotypes that ranged from simple to compound synostoses. Histologically, the osteogenic fronts of abnormally closing/closed sutures in these animals revealed calvarial overgrowth and overlap along with increased osteoblast differentiation and reduced cell proliferation. Furthermore, anomalies were restricted to calvarial bone, despite generalized, non-tissue-specific overexpression of Nell-1. In vitro, Nell-1 overexpression accelerated calvarial osteoblast differentiation and mineralization under normal culture conditions. Moreover, Nell-1 overexpression in osteoblasts was sufficient to promote alkaline phosphatase expression and micronodule formation. Conversely, downregulation of Nell-1 inhibited osteoblast differentiation in vitro. In summary, Nell-1 overexpression induced calvarial overgrowth resulting in premature suture closure in a rodent model. Nell-1, therefore, has a novel role in CS development, perhaps as part of a complex chain of events resulting in premature suture closure. On a cellular level, Nell-1 expression may modulate and be both sufficient and required for osteoblast differentiation.
AB - Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS), one of the most common congenital craniofacial deformities. Here we describe the creation and analysis of transgenic mice overexpressing Nell-1. Nell-1 transgenic animals exhibited CS-like phenotypes that ranged from simple to compound synostoses. Histologically, the osteogenic fronts of abnormally closing/closed sutures in these animals revealed calvarial overgrowth and overlap along with increased osteoblast differentiation and reduced cell proliferation. Furthermore, anomalies were restricted to calvarial bone, despite generalized, non-tissue-specific overexpression of Nell-1. In vitro, Nell-1 overexpression accelerated calvarial osteoblast differentiation and mineralization under normal culture conditions. Moreover, Nell-1 overexpression in osteoblasts was sufficient to promote alkaline phosphatase expression and micronodule formation. Conversely, downregulation of Nell-1 inhibited osteoblast differentiation in vitro. In summary, Nell-1 overexpression induced calvarial overgrowth resulting in premature suture closure in a rodent model. Nell-1, therefore, has a novel role in CS development, perhaps as part of a complex chain of events resulting in premature suture closure. On a cellular level, Nell-1 expression may modulate and be both sufficient and required for osteoblast differentiation.
UR - http://www.scopus.com/inward/record.url?scp=0036738422&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036738422&partnerID=8YFLogxK
U2 - 10.1172/JCI200215375
DO - 10.1172/JCI200215375
M3 - Article
C2 - 12235118
AN - SCOPUS:0036738422
VL - 110
SP - 861
EP - 870
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -