| Budget Amount *help |
¥3,530,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
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
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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
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