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首页> 外文期刊>Cell death and differentiation >A novel PPARγ2 modulator sLZIP controls the balance between adipogenesis and osteogenesis during mesenchymal stem cell differentiation.
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A novel PPARγ2 modulator sLZIP controls the balance between adipogenesis and osteogenesis during mesenchymal stem cell differentiation.

机译：新型PPARγ2调节剂sLZIP控制间充质干细胞分化过程中脂肪生成和成骨之间的平衡。

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Mesenchymal stem cells (MSCs), also known as multipotent stromal cells, are used in clinical trials. However, the use of MSCs for medical treatment of patients poses a potential problem due to the possibility of transdifferentiation into unwanted tissues. Disruption of the balance during MSC differentiation leads to obesity, skeletal fragility, and osteoporosis. Differentiation of MSCs into either adipocytes or osteoblasts is transcriptionally regulated by the two key transcription factors PPARγ2 and Runx2. PPARγ2 is highly expressed during adipocyte differentiation and regulates expression of genes involved in adipogenesis. Runx2 induces osteogenic gene expression and, thereby, increases osteoblast differentiation. Although transcriptional modulation of PPARγ2 has been investigated in adipogenesis, the underlying molecular mechanisms to control the balance between adipogenesis and osteogenesis in MSCs remain unclear. In this study, the role of sLZIP in regulation of PPARγ2 transcriptional activation was investigated along with sLZIP's involvement in differentiation of MSCs into adipocytes and osteoblasts. sLZIP interacts with PPARγ2 and functions as a corepressor of PPARγ2. sLZIP enhances formation of the PPARγ2 corepressor complex through specific interaction with HDAC3, resulting in suppression of PPARγ2 transcriptional activity. We found that sLZIP prevents expression of PPARγ2 target genes and adipocyte differentiation both in vitro and in vivo. sLZIP also upregulates Runx2 transcriptional activity via inhibition of PPARγ2 activity, and promotes osteoblast differentiation. sLZIP transgenic mice exhibited enhanced bone mass and density, compared with wild-type mice. These results indicate that sLZIP has a critical role in the regulation of osteogenesis and bone development. However, sLZIP does not affect chondrogenesis and osteoclastogenesis. We propose that sLZIP is a novel PPARγ2 modulator for control of the balance between adipogenesis and osteogenesis during MSC differentiation, and that sLZIP can be used as a therapeutic target molecule for treatment of obesity, osteodystrophy, and osteoporosis.
机译：间充质干细胞（MSC），也称为多能基质细胞，用于临床试验。但是，由于将MSCs转分化为不需要的组织，因此将MSC用于患者的医学治疗会引起潜在的问题。 MSC分化过程中平衡的破坏导致肥胖，骨骼脆性和骨质疏松症。 MSCs向脂肪细胞或成骨细胞的分化受两个关键转录因子PPARγ2和Runx2的转录调控。 PPARγ2在脂肪细胞分化期间高表达，并调节参与脂肪形成的基因的表达。 Runx2诱导成骨基因表达，从而增加成骨细胞分化。尽管已经在脂肪形成中研究了PPARγ2的转录调节，但是尚不清楚控制MSC中脂肪形成和成骨之间平衡的潜在分子机制。在这项研究中，研究了sLZIP在调节PPARγ2转录激活中的作用，以及sLZIP参与将MSC分化为脂肪细胞和成骨细胞的过程。 sLZIP与PPARγ2相互作用，并充当PPARγ2的核心加压因子。 sLZIP通过与HDAC3的特异性相互作用来增强PPARγ2共加压复合物的形成，从而抑制PPARγ2转录活性。我们发现，sLZIP可以在体外和体内阻止PPARγ2靶基因的表达和脂肪细胞的分化。 sLZIP还通过抑制PPARγ2活性来上调Runx2转录活性，并促进成骨细胞分化。与野生型小鼠相比，sLZIP转基因小鼠表现出增强的骨量和密度。这些结果表明，sLZIP在调节成骨和骨骼发育中具有关键作用。但是，sLZIP不会影响软骨生成和破骨细胞生成。我们提出sLZIP是一种新型PPARγ2调节剂，用于控制MSC分化过程中脂肪形成和成骨之间的平衡，并且sLZIP可用作治疗肥胖，骨营养不良和骨质疏松症的治疗靶分子。

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