Sophocleous Antonia, Sims Andrew H, Idris Aymen I, Ralston Stuart H
Rheumatology and Bone Research Group, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.
Calcif Tissue Int. 2014 Apr;94(4):423-32. doi: 10.1007/s00223-013-9823-6. Epub 2013 Dec 27.
Previous studies have shown that the skeletal consequences of cannabinoid receptor deficiency differ in different strains of mice. In order to explore the mechanisms responsible, we analysed global gene expression in bone from wild-type CD1 mice and littermates with targeted inactivation of the type 2 cannabinoid receptor (Cnr2 (-/-)) and compared the results with those obtained from a similar analysis of wild-type and Cnr2 (-/-) C57BL/6 mice. Trabecular bone volume was increased in Cnr2 (-/-) CD1 mice compared with wild-type littermates but decreased in Cnr2 (-/-) C57BL/6 mice. Microarray analysis identified 354 genes in which substantial differences in gene expression (>1.5-fold) were observed that were specifically affected by Cnr2 deficiency. Bioinformatic analysis of data from wild-type mice of each strain revealed Cnr2-dependent differences in expression of genes clustering within the gene ontology (GO) terms immune response (p < 0.0001), positive regulation of response to stimulus (p < 0.0001), nucleotide binding (p = 0.002), and ribonucleotide binding (p = 0.003). Bioinformatic analysis of data from Cnr2 (-/-) mice of each strain revealed associations between GO terms corresponding to the extracellular region (p = 0.002), the cell surface (p = 0.02), antigen binding (p = 0.03), external side of plasma membrane (p = 0.04), and regulation of the force of heart contraction (p = 0.04). We conclude that Cnr2 deficiency affects expression of a large number of genes in different strains of mice, and that these differences are likely to be responsible in part for the differences in skeletal phenotype that we and others have observed in mice with defective cannabinoid receptor signalling in different genetic backgrounds.
先前的研究表明，大麻素受体缺乏对骨骼的影响在不同品系的小鼠中有所不同。为了探究其背后的机制，我们分析了野生型CD1小鼠以及2型大麻素受体（Cnr2 (-/-)）基因敲除的同窝小鼠骨骼中的整体基因表达情况，并将结果与对野生型和Cnr2 (-/-) C57BL/6小鼠进行类似分析所得到的结果进行比较。与野生型同窝小鼠相比，Cnr2 (-/-) CD1小鼠的骨小梁体积增加，而Cnr2 (-/-) C57BL/6小鼠的骨小梁体积减少。微阵列分析确定了354个基因，这些基因的表达存在显著差异（>1.5倍），且受到Cnr2缺乏的特异性影响。对每个品系野生型小鼠的数据进行生物信息学分析发现，在基因本体（GO）术语免疫反应（p < 0.0001）、对刺激反应的正调控（p < 0.0001）、核苷酸结合（p = 0.002）和核糖核苷酸结合（p = 0.003）内聚类的基因表达存在Cnr2依赖性差异。对每个品系Cnr2 (-/-)小鼠的数据进行生物信息学分析发现，GO术语与细胞外区域（p = 0.002）、细胞表面（p = 0.02）、抗原结合（p = 0.03）、质膜外侧（p = 0.04）以及心脏收缩力调节（p = 0.04）之间存在关联。我们得出结论，Cnr2缺乏会影响不同品系小鼠中大量基因的表达，而这些差异可能部分导致了我们和其他人在不同遗传背景下大麻素受体信号缺陷小鼠中观察到的骨骼表型差异。
