Marrow adipocytes inhibit the differentiation of mesenchymal stem cells into osteoblasts via suppressing BMP-signaling.
Marrow adipocytes inhibit the differentiation of mesenchymal stem cells into osteoblasts via suppressing BMP-signaling.
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DOI：
10.1186/s12929-017-0321-4
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发表时间：
2017-02-07
影响因子：
11
通讯作者：
Abdallah BM
中科院分区：
文献类型：
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作者：
Abdallah BM
在许多与骨丢失相关的疾病中，骨形成减少与骨髓脂肪增加有关，包括衰老、绝经后和神经性厌食症。一些证据表明，旁分泌介质对骨髓间充质(骨骼)干细胞(BMSCs)的成骨和成脂具有调节作用。本研究旨在探讨脂肪细胞分泌因子对骨髓间充质干细胞增殖和成骨细胞分化的影响。无血清条件培养液(CM-ADIPO)取自基质ST2细胞来源的脂肪细胞。通过细胞存活率、碱性磷酸酶(ALP)活性定量测定、茜素红基质矿化染色和成骨基因芯片表达，观察CM-Adipo对原代小鼠BMSCs增殖和成骨细胞分化的影响。用Western印迹分析和基因报告实验检测CM-ADPO对BMPs和NF-κB信号通路的调节作用。与CM对照组相比，CM-Adipo对原代mBMSCs的细胞存活/增殖无明显影响。另一方面，CM-Adipo以剂量依赖的方式显著抑制mBMSCs向成骨细胞方向的迁移。CM-ADIPO能显著抑制BMP-2诱导的成骨细胞分化，并能激活炎性的NF-κB信号转导通路。有趣的是，用NF-κB途径的选择性抑制剂BAY11-770682处理骨髓间充质干细胞，显示CM-ADIPO对骨形态发生蛋白2诱导的骨髓间充质干细胞成骨分化的抑制作用。我们的研究结果表明，骨髓脂肪细胞通过阻断BMPs信号通路对骨髓间充质干细胞的成骨分化起旁分泌抑制作用，其机制是通过脂肪因子诱导的NF-κB途径激活。本文的在线版本(doi：10.1186/s12929-0170321-4)包含补充材料，授权用户可以使用。
Reduced bone formation is associated with increased bone marrow fat in many bone-loss related diseases including aging, post-menopause, and anorexia nervosa. Several lines of evidence suggested the regulation of osteogenesis and adipogenesis of the bone marrow-derived mesenchymal (skeletal) stem cells (BMSCs) by paracrine mediators. This study aimed to investigate the impact of adipocytes-secreted factors on the cell proliferation and osteoblast differentiation of BMSCs. Serum free conditioned medium (CM-Adipo) was collected from stromal ST2 cells-derived adipocytes. Cell viability, quantitative alkaline phosphatase (ALP) activity assay, Alizarin red staining for matrix mineralization and osteogenic gene array expression were performed to determine the effect of CM-Adipo on cell proliferation and osteoblast differentiation of primary murine BMSCs (mBMSCs). Regulation of BMPs and NF-κB signaling pathways by CM-Adipo were detected by Western blot analysis and gene reporter assay. CM-Adipo showed no effect on cell viability/proliferation of primary mBMSCs as compared to CM-control. On the other hand, CM-Adipo significantly inhibited the commitment of mBMSCs into osteoblastic cell lineage in dose-dependent manner. CM-Adipo was found to dramatically inhibit the BMP2-induced osteoblast differentiation and to activate the inflammatory NF-κB signaling in mBMSCs. Interestingly, treatment of mBMSCs with the selective inhibitor of NF-κB pathway, BAY11-770682, showed to retrieve the inhibitory effect of CM-Adipo on BMP2-induced osteoblast differentiation in mBMSCs. Our data demonstrated that the marrow adipocytes exert paracrine inhibitory effect on the osteoblast differentiation of mBMSCs by blocking BMPs signaling in a mechanism mediated by adipokines-induced NF-κB pathway activation. The online version of this article (doi:10.1186/s12929-017-0321-4) contains supplementary material, which is available to authorized users.