In vivo impact of a 4 bp deletion mutation in the DLX3 gene on bone development.
In vivo impact of a 4 bp deletion mutation in the DLX3 gene on bone development.
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DOI：
10.1016/j.ydbio.2008.10.014
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发表时间：
2009-01-01
影响因子：
2.7
通讯作者：
Hart TC
中科院分区：
文献类型：
--
作者：
Choi SJ;Roodman GD;Feng JQ;Song IS;Amin K;Hart PS;Wright JT;Haruyama N;Hart TC
远端无3 （DLX3）基因突变是毛牙骨综合征的病因。为了研究DLX3突变体对骨发育的体内影响，我们建立了由小鼠2.3 Col1A1启动子驱动表达c.571_574delGGGG DLX-3基因突变（MT-DLX3）的转基因（TG）小鼠。微计算机断层扫描分析显示TG小鼠股骨骨小梁体积和骨密度明显增加。在离体实验中，TG小鼠骨髓基质细胞向成骨细胞分化增强，骨形成标志物表达水平升高。然而，在体内荧光双标记实验中，TG小鼠没有表现出增强的动态骨形成率。在破骨因子存在下，TG小鼠骨髓单核细胞的破骨分化能力降低，远端干骺端小梁骨表面TRAP（+）破骨细胞数量明显减少。TG小鼠血清中TRACP 5b和CTX水平显著降低，IFN-γ水平显著升高。这些数据表明，IFN-γ水平的增加会降低破骨细胞骨吸收活性，从而导致TG小鼠小梁骨体积和矿物质密度的增加。这些数据表明，这种DLX-3突变在破骨细胞分化和骨吸收中起着新的作用。
Distal-less 3 (DLX3) gene mutations are etiologic for Tricho-Dento-Osseous syndrome. To investigate the in vivo impact of mutant DLX3 on bone development, we established transgenic (TG) mice expressing the c.571_574delGGGG DLX-3 gene mutation (MT-DLX3) driven by a mouse 2.3 Col1A1 promoter. Microcomputed tomographic analyses demonstrated markedly increased trabecular bone volume and bone mineral density in femora from TG mice. In ex vivo experiments, TG mice showed enhanced differentiation of bone marrow stromal cells to osteoblasts and increased expression levels of bone formation markers. However, TG mice did not show enhanced dynamic bone formation rates in in vivo fluorochrome double labeling experiments. Osteoclastic differentiation capacities of bone marrow monocytes were reduced in TG mice in the presence of osteoclastogenic factors and the numbers of TRAP(+) osteoclasts on distal metaphyseal trabecular bone surfaces were significantly decreased. TRACP 5b and CTX serum levels were significantly decreased in TG mice, while IFN-γ levels were significantly increased. These data demonstrate that increased levels of IFN-γ decrease osteoclast bone resorption activities, contributing to the enhanced trabecular bone volume and mineral density in these TG mice. These data suggest a novel role for this DLX-3 mutation in osteoclast differentiation and bone resorption.