Gene expression analysis in human osteoblasts exposed to dexamethasone identifies altered developmental pathways as putative drivers of osteoporosis.
Gene expression analysis in human osteoblasts exposed to dexamethasone identifies altered developmental pathways as putative drivers of osteoporosis.
复制标题
暴露于地塞米松的人类成骨细胞中的基因表达分析鉴定出改变的发育途径是骨质疏松的推定驱动因素。
DOI：
10.1186/1471-2474-8-12
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发表时间：
2007-02-12
影响因子：
2.3
通讯作者：
Doran PP
中科院分区：
文献类型：
--
作者：
Hurson CJ;Butler JS;Keating DT;Murray DW;Sadlier DM;O'Byrne JM;Doran PP
骨质疏松症是一种骨密度降低的疾病，在西方世界是一个重大的、日益严重的负担。人口结构老龄化和糖皮质激素的治疗应用在很大程度上导致了该病发病率的增加。尽管在过去的几年里进行了大量的研究工作，但支持骨质疏松症发生和发展的确切分子机制仍有待阐明。这意味着在治疗策略上没有出现重大进展，关节置换手术是治疗的主要手段。在这项研究中，我们使用了一种综合的基因组学图谱和基于计算生物学的策略来识别关键的成骨细胞基因和基因簇，这些基因和基因簇的表达会因地塞米松的作用而改变。原代人成骨细胞在体外暴露于地塞米松，并完成基于基因芯片的转录组分析。这些研究确定了大约500个表达改变的成骨细胞基因。转录组的功能特征表明，发育网络被重新激活，106个与发育相关的基因被发现存在差异调控。通过实时定量聚合酶链式反应证实了WNT信号通路成员Frizzled2、Frizzled7、Dkk1和WNT5B的协同改变。WNT途径是骨形成和骨细胞分化的关键调节因子。该途径的重新激活可能导致成骨细胞活性改变，导致骨密度降低，这是骨质疏松的病理标志。这里的数据支持了这样一种假设，即发育途径的改变推动了骨质疏松症的开始和进展。
Osteoporosis, a disease of decreased bone mineral density represents a significant and growing burden in the western world. Aging population structure and therapeutic use of glucocorticoids have contributed in no small way to the increase in the incidence of this disease. Despite substantial investigative efforts over the last number of years the exact molecular mechanism underpinning the initiation and progression of osteoporosis remain to be elucidated. This has meant that no significant advances in therapeutic strategies have emerged, with joint replacement surgery being the mainstay of treatment. In this study we have used an integrated genomics profiling and computational biology based strategy to identify the key osteoblast genes and gene clusters whose expression is altered in response to dexamethasone exposure. Primary human osteoblasts were exposed to dexamethasone in vitro and microarray based transcriptome profiling completed. These studies identified approximately 500 osteoblast genes whose expression was altered. Functional characterization of the transcriptome identified developmental networks as being reactivated with 106 development associated genes found to be differentially regulated. Pathway reconstruction revealed coordinate alteration of members of the WNT signaling pathway, including frizzled-2, frizzled-7, DKK1 and WNT5B, whose differential expression in this setting was confirmed by real time PCR. The WNT pathway is a key regulator of skeletogenesis as well as differentiation of bone cells. Reactivation of this pathway may lead to altered osteoblast activity resulting in decreased bone mineral density, the pathological hallmark of osteoporosis. The data herein lend weight to the hypothesis that alterations in developmental pathways drive the initiation and progression of osteoporosis.