Neural Crest-Specific TSC1 Deletion in Mice Leads to Sclerotic Craniofacial Bone Lesion.
Neural Crest-Specific TSC1 Deletion in Mice Leads to Sclerotic Craniofacial Bone Lesion.
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DOI：
10.1002/jbmr.2447
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发表时间：
2015-07
影响因子：
6.2
通讯作者：
Liu, Fei
中科院分区：
文献类型：
--
作者：
Fang, Fang;Sun, Shaogang;Wang, Li;Guan, Jun-Lin;Giovannini, Marco;Zhu, Yuan;Liu, Fei
结节性硬化症(TSC)是一种常染色体显性遗传病，由TSC1或TSC2突变引起。TSC具有较高的骨性表现，如颅面部硬化性病变。然而，复制TSC颅面骨损伤的动物模型尚未被描述。TSC1的作用和TSC1功能障碍在骨中的后遗症尚不清楚。在这项研究中，我们建立了一种TSC的小鼠模型，该模型在神经脊来源的(NCD)细胞中缺失了TSC1，该细胞概括了TSC的硬化性颅面骨病变。对这一小鼠模型的分析表明，TSC1缺失导致NCD骨骼中mTORC1信号增强，骨形成的增加是骨量异常增加的原因。谱系图谱显示，TSC1缺陷的NCD细胞过度填充NCD骨。从机制上讲，出生后早期成骨细胞的过度增殖是成骨细胞池增加的原因。有趣的是，出生后早期使用mTORC1抑制剂雷帕霉素可以完全挽救异常的骨量，但晚期治疗不能。我们的数据表明，NCD细胞中增强的mTOR信号可以通过扩大骨祖细胞池来增加骨量，这可能是在TSC患者中观察到硬化性骨损害的原因。
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. TSC has high frequency of osseous manifestations such as sclerotic lesions in the craniofacial region. However, an animal model that replicates TSC craniofacial bone lesions has not yet been described. The roles of Tsc1 and the sequelae of Tsc1 dysfunction in bone are unknown. In this study, we generated a mouse model of TSC with a deletion of Tsc1 in neural crest-derived (NCD) cells that recapitulated the sclerotic craniofacial bone lesions in TSC. Analysis of this mouse model demonstrated that TSC1 deletion led to enhanced mTORC1 signaling in NCD bones and the increase in bone formation is responsible for the aberrantly increased bone mass. Lineage mapping revealed that TSC1 deficient NCD cells overpopulated the NCD bones. Mechanistically, hyperproliferation of osteoprogenitors at an early postnatal stage accounts for the increased osteoblast pool. Intriguingly, early postnatal treatment with rapamycin, an mTORC1 inhibitor, can completely rescue the aberrant bone mass, but late treatment cannot. Our data suggest that enhanced mTOR signaling in NCD cells can increase bone mass through enlargement of the osteoprogenitor pool, which likely explains the sclerotic bone lesion observed in TSC patients.
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DOI：
10.1046/j.1440-1673.2002.01098.x
发表时间：
2002-12-01
期刊：
Australasian radiology
影响因子：
--
作者：
Morris, B S;Garg, A;Jadhav, P J
通讯作者：
Jadhav, P J
影响因子：
5.3
作者：
Fingar, DC;Richardson, CJ;Blenis, J
通讯作者：
Blenis, J
影响因子：
1.7
作者：
Isomoto, Shinji;Hattori, Koji;Takakura, Yoshinori
通讯作者：
Takakura, Yoshinori
影响因子：
6.2
作者：
Liu, Fei;Fang, Fang;Yuan, Hebao;Yang, Dongye;Chen, Yongqiang;Williams, Linford;Goldstein, Steven A.;Krebsbach, Paul H.;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
影响因子：
7.5
作者：
Faghihi, F.;Eslaminejad, M. Baghaban;Salekdeh, G. H.
通讯作者：
Salekdeh, G. H.