血清胰岛素样生长因子-I水平较低的同源近交系小鼠体脂增加、骨矿物质密度降低且成骨细胞分化程序改变。
Congenic mice with low serum IGF-I have increased body fat, reduced bone mineral density, and an altered osteoblast differentiation program.
作者信息
Rosen Clifford J, Ackert-Bicknell Cheryl L, Adamo Martin L, Shultz Kathy L, Rubin Janet, Donahue Leah Rae, Horton Lindsay G, Delahunty Krista M, Beamer Wesley G, Sipos Jennifer, Clemmons David, Nelson Tracy, Bouxsein Mary L, Horowitz Mark
机构信息
The Jackson Laboratory, Bar Harbor, ME, USA.
出版信息
Bone. 2004 Nov;35(5):1046-58. doi: 10.1016/j.bone.2004.07.008.
Targeted gene studies have demonstrated the importance of insulin-like growth factor-I (IGF-I) for osteoblast (OB) differentiation and the acquisition of peak bone mineral density (BMD). The skeletal response to allelic differences in IGF-I expression can also be measured in vivo, using congenic mice. We created a congenic strain with reduced (approximately 20%) circulating IGF-I (C3H.B6-6T [6T]) by backcrossing a small genomic region (30 cM) of Chromosome 6 (Chr6) from C3H/HeJ (C3H) onto a C57Bl/6J (B6) background. 6T female mice have lower serum IGF-I (P<0.001 vs. B6) but similar growth hormone (GH) and serum IGF binding protein (IGFBP) concentrations as B6. At 16 weeks of age, congenics have greater body fat (P<0.02 vs. B6) despite less total body weight, and exhibit smaller femoral cross-sectional size (P=0.001), reduced cortical thickness (P<0.001) and lower trabecular BV/TV (P<0.05) than B6. 6T mice also have suppressed serum leptin (P<0.01), but compared to B6 have similar markers of bone resorption (i.e., urine CTx and serum TRAP 5B). At 8 weeks of age, skeletal IGF-I mRNA from long bones was reduced by 40% (P<0.05) as were liver mRNA transcripts (i.e., 50%, P<0.01). Osteoblast progenitors from the bone marrow of 6T mice formed less colony forming unit fibroblasts by crystal violet staining than B6 (P<0.007) and had significantly reduced alkaline phosphatase-positive colonies than B6(P<0.0001). In addition, staining of bone marrow with oil red O revealed greater numbers of adipocytes in 6T than B6. Several candidate genes in the Chr6 QTL were excluded by lack of strain-related expression differences in bone, but genes positively regulating adipocyte differentiation including Alox 5 and PPAR-gamma require further study as either "pathway" or candidate genes. In summary, allelic differences in a QTL on Chr6 result in altered IGF-I gene expression, changes in OB lineage allocation, and reduced peak bone mass. Congenic mice are useful models not only for mapping genes related to bone mass but also for elucidating the biology underlying various skeletal phenotypes associated with more subtle manipulation of the mouse genome.
靶向基因研究已证明胰岛素样生长因子-I（IGF-I）对成骨细胞（OB）分化及获得峰值骨矿物质密度（BMD）的重要性。利用同源基因小鼠，也可在体内测量骨骼对IGF-I表达中等位基因差异的反应。我们通过将C3H/HeJ（C3H）6号染色体（Chr6）上一个小的基因组区域（30 cM）回交至C57Bl/6J（B6）背景，创建了一个循环IGF-I降低（约20%）的同源基因品系（C3H.B6-6T [6T]）。6T雌性小鼠血清IGF-I水平较低（与B6相比，P<0.001），但生长激素（GH）和血清IGF结合蛋白（IGFBP）浓度与B6相似。16周龄时，尽管总体重较轻，但同源基因小鼠体脂更多（与B6相比，P<0.02），股骨横截面尺寸较小（P = 0.001），皮质厚度降低（P<0.001），小梁骨体积分数（BV/TV）低于B6（P<0.05）。6T小鼠血清瘦素也受到抑制（P<0.01），但与B6相比，骨吸收标志物（即尿CTX和血清TRAP 5B）相似。8周龄时，长骨的骨骼IGF-I mRNA减少了40%（P<0.05），肝脏mRNA转录本也减少了（即50%，P<0.01）。通过结晶紫染色，6T小鼠骨髓中的成骨细胞祖细胞形成的集落形成单位成纤维细胞比B6少（P<0.007），碱性磷酸酶阳性集落比B6显著减少（P<0.0001）。此外，用油红O对骨髓进行染色显示，6T小鼠中的脂肪细胞数量比B6多。Chr6数量性状基因座中的几个候选基因因在骨骼中缺乏品系相关的表达差异而被排除，但包括Alox 5和PPAR-γ在内的正向调节脂肪细胞分化的基因作为“途径”或候选基因需要进一步研究。总之，Chr6上数量性状基因座的等位基因差异导致IGF-I基因表达改变、OB谱系分配变化以及峰值骨量降低。同源基因小鼠不仅是定位与骨量相关基因的有用模型，也是阐明与小鼠基因组更精细操作相关的各种骨骼表型背后生物学机制的有用模型。
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