Tissue-nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the Alpl(-/-) mouse model of infantile hypophosphatasia.
Tissue-nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the Alpl(-/-) mouse model of infantile hypophosphatasia.
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DOI：
10.1016/j.bone.2014.06.040
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发表时间：
2014-10
期刊：
影响因子：
4.1
通讯作者：
Hatch, Nan E.
中科院分区：
文献类型：
--
作者：
Liu, Jin;Nam, Hwa Kyung;Campbell, Cassie;Gasque, Kellen Cristina da Silva;Millan, Jose Luis;Hatch, Nan E.
组织非特异性碱性磷酸酶（TNAP）是一种存在于矿化细胞及其衍生基质囊泡表面的酶，可促进羟基磷灰石晶体生长。低磷酸酯酶症（Hypophosphatasia，HPP）是一种代谢异常疾病，其特征在于由于编码TNAP的基因（Alpl）的功能丧失突变而导致的佝偻病或骨软化，其取决于发病年龄。颅缝早闭在患有HPP和其他形式的佝偻病的婴儿中很普遍，但颅缝早闭在这些疾病中如何发展尚不清楚。目的：由于颅缝早闭具有高发病率，我们正在研究Alpl−/−小鼠的颅面骨骼异常，以建立这些小鼠作为HPP相关颅缝早闭的模型，并确定TNAP影响颅面骨骼发育的机制。方法：对颅骨、颅缝、颅底畸形进行显微CT和组织学分析。使用数字卡尺定量颅面形状异常。TNAP特异性shRNA抑制MC 3 T3 E1（C4）颅骨细胞中TNAP的表达。分析细胞矿化、基因表达、增殖、凋亡、基质沉积和细胞粘附的变化。结果：Alpl-/-小鼠的颅面形状异常，表明前后生长有限。颅缝早闭以骨性冠状缝融合的形式出现在出生后三周。Alpl−/−小鼠在出生后两周内也表现出明显的颅骨和颅底组织学异常，包括生长板、皮质骨和骨小梁。TNAP表达被shRNA抑制的颅骨细胞的分析表明，TNAP缺乏促进异常成骨细胞基因表达，减少基质沉积，减少增殖，增加凋亡和增加细胞粘附。结论：这些发现表明，Alpl−/−小鼠表现出与HPP婴儿相似的颅面骨骼表型，包括在骨矿化严重减少的背景下的真正骨颅缝早闭。未来的研究将需要确定TNAP缺乏症和其他形式的佝偻病是否直接通过颅骨细胞行为异常或间接由于颅底生长不足而促进颅缝早闭。
Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown. Objectives: Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl−/− mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. Methods: Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. Results: Alpl−/− mice feature craniofacial shape abnormalities suggestive of limited anterior-posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl−/− mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. Conclusions: These findings demonstrate that Alpl−/− mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base.
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DOI：
10.1359/jbmr.091023
发表时间：
2010-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Ciancaglini P;Yadav MC;Simão AM;Narisawa S;Pizauro JM;Farquharson C;Hoylaerts MF;Millán JL
通讯作者：
Millán JL
影响因子：
6
作者：
Anderson, HC;Harmey, D;Millán, JL
通讯作者：
Millán, JL
影响因子：
168.9
作者：
Elder, Charlotte Jane;Bishop, Nicholas J.
通讯作者：
Bishop, Nicholas J.
影响因子：
1.4
作者：
Collmann, H.;Mornet, E.;Girschick, H.
通讯作者：
Girschick, H.
影响因子：
6
作者：
Harmey, D;Hessle, L;Millán, JL
通讯作者：
Millán, JL