Expression profiling of Dexamethasone-treated primary chondrocytes identifies targets of glucocorticoid signalling in endochondral bone development.
Expression profiling of Dexamethasone-treated primary chondrocytes identifies targets of glucocorticoid signalling in endochondral bone development.
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DOI：
10.1186/1471-2164-8-205
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发表时间：
2007-07-01
期刊：
影响因子：
4.4
通讯作者：
Beier F
中科院分区：
文献类型：
--
作者：
James CG;Ulici V;Tuckermann J;Underhill TM;Beier F
糖皮质激素(GCs)是广泛使用的抗炎药物。虽然在临床实践中有用，但服用GCs的患者经常遭受骨骼副作用的影响，包括儿童和青少年的生长迟缓，以及成年人的骨骼质量下降。在生理水平上，GCs参与了软骨形成和成骨细胞分化的调节，以及维持软骨和骨的动态平衡。在原代肢芽间充质微团培养的微阵列筛选中，我们发现糖皮质激素受体(GR)是软骨细胞肥大的潜在调节因子。在软骨形成中GC调控的一些靶点是已知的，但药物GC剂量对软骨细胞基因表达的整体影响还没有得到全面的评估。这项研究系统地鉴定了合成GR激动剂地塞米松(DEX)处理6小时和24小时的胚胎生长板软骨细胞中GC靶基因的谱。对该数据集进行常规分析和基因集浓缩分析(GSEA)。在DEX条件下，与新陈代谢相关的转录本与细胞外基质基因一起被丰富。相反，生长因子和细胞因子的一部分与地塞米松治疗呈负相关。将地塞米松诱导的基因表达数据与微团培养中基因表达的发育变化进行比较，发现了另一层复杂性，即地塞米松维持某些软骨细胞标记基因的表达，同时抑制促进软骨模板血管形成和最终骨化的因素。综上所述，这些结果为深入了解DEX下游在原代软骨细胞中的作用机制和主要分子类别提供了洞察力。此外，将我们的数据与其他细胞类型的地塞米松治疗的微阵列研究进行比较，表明大多数地塞米松的影响是组织特异性的。本研究为药物GC对软骨细胞基因转录的影响提供了新的见解，并为后续的功能研究奠定了基础。
Glucocorticoids (GCs) are widely used anti-inflammatory drugs. While useful in clinical practice, patients taking GCs often suffer from skeletal side effects including growth retardation in children and adolescents, and decreased bone quality in adults. On a physiological level, GCs have been implicated in the regulation of chondrogenesis and osteoblast differentiation, as well as maintaining homeostasis in cartilage and bone. We identified the glucocorticoid receptor (GR) as a potential regulator of chondrocyte hypertrophy in a microarray screen of primary limb bud mesenchyme micromass cultures. Some targets of GC regulation in chondrogenesis are known, but the global effects of pharmacological GC doses on chondrocyte gene expression have not been comprehensively evaluated. This study systematically identifies a spectrum of GC target genes in embryonic growth plate chondrocytes treated with a synthetic GR agonist, dexamethasone (DEX), at 6 and 24 hrs. Conventional analysis of this data set and gene set enrichment analysis (GSEA) was performed. Transcripts associated with metabolism were enriched in the DEX condition along with extracellular matrix genes. In contrast, a subset of growth factors and cytokines were negatively correlated with DEX treatment. Comparing DEX-induced gene expression data to developmental changes in gene expression in micromass cultures revealed an additional layer of complexity in which DEX maintains the expression of certain chondrocyte marker genes while inhibiting factors that promote vascularization and ultimately ossification of the cartilaginous template. Together, these results provide insight into the mechanisms and major molecular classes functioning downstream of DEX in primary chondrocytes. In addition, comparison of our data with microarray studies of DEX treatment in other cell types demonstrated that the majority of DEX effects are tissue-specific. This study provides novel insights into the effects of pharmacological GC on chondrocyte gene transcription and establishes the foundation for subsequent functional studies.
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影响因子：
2.3
作者：
Agoston H;Baybayan L;Beier F
通讯作者：
Beier F
影响因子：
--
作者：
De Benedetti, Fabrizio;Rucci, Nadia;Teti, Anna
通讯作者：
Teti, Anna
影响因子：
64.5
作者：
Bookout, Angie L.;Jeong, Yangsik;Mangelsdorf, David J.
通讯作者：
Mangelsdorf, David J.
影响因子：
5.8
作者：
Abu, EO;Horner, A;Compston, JE
通讯作者：
Compston, JE
DOI：
10.1016/s0934-8832(11)80075-2
发表时间：
1993-03-01
期刊：
MATRIX
影响因子：
--
作者：
APTE, SS;OLSEN, BR
通讯作者：
OLSEN, BR