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ACandidate Gene on Murine Chromosome 11 Regulating Peak Bone Mass

小鼠 11 号染色体上调节峰值骨量的候选基因

基本信息

批准号：
18591661
负责人：
TSUBOYAMA Tadao
金额：
$ 2.26万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591661/
关键词：
bone share bone streneth congenic mouse strain SAMP6 Cacng4 hone mass 骨粗鬆症モデル動物原因遺伝子

项目摘要

In our previous study using senescence-accelerated mouse (SAM) strains, we reported three significant loci with significant linkage to peak relative bone mass in male mice on chromosomes (Chr) 11, 13, and X (termed Pbd1, Pbd2 and Pbd3, respectively), using the F2 intercrosses of the SAMP2 and SAMP6 strains. We confirmed the existence of Pbd1 by generating a congenic strain, P6.P2-Pbd1b, which carries a 39 cM SAMP2-derived Chr11 interval on a SAMP6 genetic background.In this study, 16 subcongenic strains with smaller overlapping intervals were generated to narrow the interval, and the Pbd1 locus was narrowed down to a 10.0Mbp region.Furthermore, we analyzed the morphological features of the femoral shaft using microfocus computer tomography (μCT) and showed that the femoral cross-sectional shape of P6.P2-Pbd1b (and the other subcongenic strains with higher relative bone mass) was more compressed anteroposteriorly than that of SAMP6, which was associated with superior mechanical properti … More es. Maximum failure load and stiffness were greater in SAMP6 than in subcongenic strains with higher relative bone mass. This feature developed during bone modeling up to 16 weeks of age. Subcongenic strains with a higher relative bone mass showed significant increases in endocortical mineral apposition rate and significant reductions in periosteal mineral apposition rate at eight weeks, compared with those of SAMP6. These differences possibly produce the difference in cross-sectional shape.In Pbd1, 114 genes have been identified. Because we did not detect any differences in exon sequences of all these genes, mRNA levels of bone tissue and kidney were analyzed for all candidate genes by real-time RT-CR, and six genes have been identified as the candidates. In these genes, the expression level of Cacng4 in the kidney was notably lower in the subcongenic strains with higher relative bone mass than in SAMP6. The sequence of the 5' promoter region of Cacng4 between SAMP6 and SAMP2 revealed that there exists two SNPs in this region, and these SNPs may influence the expression level of Cacng4 in the kidney. Less

在我们以前的研究中，使用加速衰老小鼠（SAM）品系，我们报告了三个显着的基因座显着连锁峰值相对骨量在雄性小鼠染色体（Chr）11，13和X（称为Pbd 1，Pbd 2和Pbd 3，分别），使用F2杂交的SAMP 2和SAMP 6品系。本研究通过构建一个在SAMP 6遗传背景上带有39 cM的来源于SAMP 2的Chr 11间隔的同源菌株P6.P2-Pbd 1b，证实了Pbd 1的存在。我们使用微焦点计算机断层扫描（μCT）分析了股骨干的形态学特征，结果显示P6. P2-Pbd 1b股骨横截面形状（和其他具有较高相对骨量的亚同源品系）比SAMP 6更向前向后压缩，这与上级的机械性能有关， ...更多信息 es. SAMP 6的最大失效载荷和刚度大于相对骨量较高的亚同源菌株。这一特征在长达16周龄的骨建模期间发展。与SAMP 6相比，具有较高相对骨量的亚同源菌株在8周时皮质内矿物质沉积率显著增加，骨膜矿物质沉积率显著降低。在Pbd 1中，已鉴定出114个基因。因为我们没有检测到所有这些基因的外显子序列的任何差异，骨组织和肾脏的mRNA水平进行了分析，所有候选基因的实时RT-CR，和6个基因已被确定为候选人。在这些基因中，Cacng 4在肾脏中的表达水平在具有较高相对骨量的亚同源品系中显著低于SAMP 6。对SAMP 6和SAMP 2之间Cacng 4基因5'端启动子区的序列分析表明，该区域存在两个SNP位点，这些SNP位点可能影响Cacng 4在肾脏中的表达水平。少