Bone and Calcium Metabolism, Department Internal Medicine, Erasmus MC, Wytemaweg 80, Postbus 2040, 3000 CA Rotterdam, the Netherlands.
Synthetic Systems Biology, University of Amsterdam, 1081 HZ Amsterdam, the Netherlands; Molecular Cell Physiology, VU University Amsterdam, 1081 HZ Amsterdam, the Netherlands; Systems Biology, MCISB, University of Manchester, Manchester M1 7DN, UK.
Stem Cell Reports. 2017 Apr 11;8(4):947-960. doi: 10.1016/j.stemcr.2017.02.018. Epub 2017 Mar 23.
Age-related skeletal degeneration in patients with osteoporosis is characterized by decreased bone mass and occurs concomitant with an increase in bone marrow adipocytes. Using microarray expression profiling with high temporal resolution, we identified gene regulatory events in early stages of osteogenic and adipogenic lineage commitment of human mesenchymal stromal cells (hMSCs). Data analysis revealed three distinct phases when cells adopt a committed expression phenotype: initiation of differentiation (0-3 hr, phase I), lineage acquisition (6-24 hr, phase II), and early lineage progression (48-96 hr, phase III). Upstream regulator analysis identified 34 transcription factors (TFs) in phase I with a role in hMSC differentiation. Interestingly, expression levels of identified TFs did not always change and indicate additional post-transcriptional regulatory mechanisms. Functional analysis revealed that forced expression of IRF2 enhances osteogenic differentiation. Thus, IRF2 and other early-responder TFs may control osteogenic cell fate of MSCs and should be considered in mechanistic models that clarify bone-anabolic changes during clinical progression of osteoporosis.
与骨质疏松症相关的骨骼退行性病变的特征是骨量减少，同时骨髓脂肪细胞增加。我们使用具有高时间分辨率的微阵列表达谱，鉴定了人类间充质基质细胞（hMSC）成骨和成脂谱系定向早期的基因调控事件。数据分析揭示了细胞采用特定表达表型的三个不同阶段：分化起始（0-3 小时，第一阶段）、谱系获得（6-24 小时，第二阶段）和早期谱系进展（48-96 小时，第三阶段）。在第一阶段，上游调节剂分析确定了 34 种在 hMSC 分化中起作用的转录因子（TFs）。有趣的是，鉴定的 TFs 的表达水平并不总是变化，这表明存在其他转录后调控机制。功能分析显示，IRF2 的强制表达增强了成骨分化。因此，IRF2 和其他早期反应 TFs 可能控制着间充质干细胞的成骨细胞命运，在阐明骨质疏松症临床进展过程中的骨合成变化的机制模型中应予以考虑。
