Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome.
Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome.
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衰老：对 DLX3 突变导致毛齿牙骨综合征骨形成增强的新见解。
DOI：
10.1038/srep38680
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发表时间：
2016-12-07
影响因子：
4.6
通讯作者：
Feng H
中科院分区：
文献类型：
--
作者：
Zhao N;Han D;Liu H;Li Y;Wong SW;Cao Z;Xu J;Zhang X;Cai T;Wang Y;Feng H
同源结构域转录因子远端同源框3基因（DLX 3）是头发，牙齿和骨骼发育所必需的。已发现DLX 3突变导致毛发-牙-骨（TDO）综合征，其特征在于卷曲的毛发、薄凹陷的釉质和骨密度增加。在这里，我们发现DLX 3突变（c.533 A>G; Q178 R）减弱了从TDO患者分离的骨髓间充质干细胞（BMSC）的成骨潜力和衰老，为骨密度异常增加提供了分子解释。两种DLX 3突变（c.533A>G和c.571_574delGGGG）在被引入前成骨细胞MC 3 T3-E1中时延迟细胞衰老。此外，DLX 3（Q178 R）转基因小鼠中骨骼衰老和骨丢失的减弱不仅再次证实DLX 3突变（Q178 R）延迟细胞衰老，而且还防止衰老介导的骨丢失。总之，这些结果表明DLX 3突变在衰老中起功能丧失的作用。骨髓间充质干细胞的延迟衰老导致骨形成增加，通过更多代和延长功能寿命来补偿降低的成骨潜力。我们在罕见的人类遗传性疾病中的发现揭示了DLX 3涉及骨形成衰老调节的新机制。
The homeodomain transcription factor distal-less homeobox 3 gene (DLX3) is required for hair, tooth and skeletal development. DLX3 mutations have been found to be responsible for Tricho-Dento-Osseous (TDO) syndrome, characterized by kinky hair, thin-pitted enamel and increased bone density. Here we show that the DLX3 mutation (c.533 A>G; Q178R) attenuates osteogenic potential and senescence of bone mesenchymal stem cells (BMSCs) isolated from a TDO patient, providing a molecular explanation for abnormal increased bone density. Both DLX3 mutations (c.533 A>G and c.571_574delGGGG) delayed cellular senescence when they were introduced into pre-osteoblastic cells MC3T3-E1. Furthermore, the attenuated skeletal aging and bone loss in DLX3 (Q178R) transgenic mice not only reconfirmed that DLX3 mutation (Q178R) delayed cellular senescence, but also prevented aging-mediated bone loss. Taken together, these results indicate that DLX3 mutations act as a loss of function in senescence. The delayed senescence of BMSCs leads to increased bone formation by compensating decreased osteogenic potentials with more generations and extended functional lifespan. Our findings in the rare human genetic disease unravel a novel mechanism of DLX3 involving the senescence regulation of bone formation.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
2.7
作者：
Choi SJ;Roodman GD;Feng JQ;Song IS;Amin K;Hart PS;Wright JT;Haruyama N;Hart TC
通讯作者：
Hart TC
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4.8
作者：
Hassan, Mohammad Q.;Tare, Rahul S.;Lian, Jane B.
通讯作者：
Lian, Jane B.
形态学分析和与中国家族毛牙骨综合征相关的新 DLX3 突变
影响因子：
1.9
作者：
Li, Yue;Han, Dong;Feng, Hailan
通讯作者：
Feng, Hailan