PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells.
PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells.
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DOI：
10.1002/jcb.21994
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发表时间：
2009-02-01
影响因子：
4
通讯作者：
Lecka-Czemik, Beata
中科院分区：
文献类型：
--
作者：
Shockley, Keith R.;Lazarenko, Oxana P.;Czernik, Piotr J.;Rosen, Clifford J.;Churchill, Gary A.;Lecka-Czemik, Beata
罗格列酮（Rosi）是用于治疗2型糖尿病的噻唑烷二酮类药物的成员，其激活脂肪细胞特异性转录因子过氧化物酶体增殖物激活受体γ（PPARγ）。这种激活导致动物和人类的骨丢失，至少部分是由于骨髓间充质干细胞（MSC）成骨细胞分化的抑制。为了确定PPARγ2在MSC中抑制成骨细胞生成和促进脂肪生成的机制，我们分析了响应于Rosi的PPARγ2转录组。与未诱导的U-33/γ2细胞相比，将Rosi（1 μM）应用于经PPARγ2稳定转染的U-33骨髓基质细胞系（U-33/γ2）时，共产生4，252个转录变化。稳定转染空载体（U-33/c）的U-33/γ2和U-33细胞之间的差异包括7，928个转录变化，与Rosi无关。细胞类型、时间和治疗特异性基因聚类揭示了MSC谱系定型的PPARγ2转录控制的不同模式。伴随Rosi激活PPARγ2的最早变化包括对Wnt、TGFβ/BMP和G蛋白信号传导活性的影响，以及对脂肪细胞特异性基因表达和脂质代谢的持续诱导。虽然成骨细胞表型的抑制是由成骨细胞特异性信号通路的表达减少引发的，但脂肪细胞表型的诱导是由脂肪细胞特异性转录调节因子引发的。这表明，不同的机制支配抑制骨生成和刺激脂肪生成。在此发现的共表达模式表明，PPARγ2在控制成骨细胞分化中具有主导作用，并提示许多基因-基因相互作用，可能导致鉴定指导该过程的“主”调控方案。
Rosiglitazone (Rosi), a member of the thiazolidinedione class of drugs used to treat type 2 diabetes, activates the adipocyte-specific transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). This activation causes bone loss in animals and humans, at least in part due to suppression of osteoblast differentiation from marrow mesenchymal stem cells (MSC). In order to identify mechanisms by which PPARγ2 suppresses osteoblastogenesis and promotes adipogenesis in MSC, we have analyzed the PPARγ2 transcriptome in response to Rosi. A total of 4,252 transcriptional changes resulted when Rosi (1 μM) was applied to the U-33 marrow stromal cell line stably transfected with PPARγ2 (U-33/γ2) as compared to non-induced U-33/γ2 cells. Differences between U-33/γ2 and U-33 cells stably transfected with empty vector (U-33/c) comprised 7,928 transcriptional changes, independent of Rosi. Cell type-, time- and treatment-specific gene clustering uncovered distinct patterns of PPARγ2 transcriptional control of MSC lineage commitment. The earliest changes accompanying Rosi activation of PPARγ2 included effects on Wnt, TGFβ/BMP and G-protein signaling activities, as well as sustained induction of adipocyte-specific gene expression and lipid metabolism. While suppression of osteoblast phenotype is initiated by a diminished expression of osteoblast-specific signaling pathways, induction of the adipocyte phenotype is initiated by adipocyte-specific transcriptional regulators. This indicates that distinct mechanisms govern the repression of osteogenesis and the stimulation of adipogenesis. The co-expression patterns found here indicate that PPARγ2 has a dominant role in controlling osteoblast differentiation and suggests numerous gene-gene interactions that could lead to the identification of a “master” regulatory scheme directing this process.
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影响因子：
4.8
作者：
Ali, AA;Weinstein, RS;Jilka, RL
通讯作者：
Jilka, RL
影响因子：
6.2
作者：
Ackert-Bicknell, Cheryl L.;Demissie, Serkalem;Rosen, Clifford J.
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Rosen, Clifford J.
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4.6
作者：
Escalante-Alcalde, D;Hernandez, L;Stewart, CL
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Stewart, CL
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作者：
Abe, E;Yamamoto, M;Manolagas, SC
通讯作者：
Manolagas, SC
影响因子：
15.9
作者：
Akune, T;Ohba, S;Kawaguchi, H
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Kawaguchi, H