TSG-6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF-κB signaling pathway
TSG-6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF-κB signaling pathway
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骨髓间充质干细胞分泌的TSG-6通过抑制TLR2/NF-κB信号通路减轻椎间盘退变
DOI：
10.1038/s41374-018-0036-5
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发表时间：
2018-06-01
影响因子：
5
通讯作者：
Wang, Xiangrui
中科院分区：
文献类型：
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作者：
Yang, Hao;Tian, Weitian;Wang, Xiangrui
炎症与椎间盘退变（IDD）相关。最近的证据表明，由骨髓间充质干细胞（BMSCs）分泌的TNF-α刺激的基因6蛋白（TSG-6）显示出抑制多种疾病中的炎症过程的显著能力。然而，目前还不清楚BMSCs是否通过分泌TSG-6发挥其对IDD的治疗作用。本研究在体内外研究了骨髓间充质干细胞和TSG-6对IDD的影响，并探讨了其可能的作用机制。我们发现BMSCs和TSG-6降低了IL-1 β处理的髓核细胞（NPC）中MMP-3和MMP-13的表达，并增加了II型胶原和聚集蛋白聚糖的表达，但当TSG-6表达沉默时，BMSCs和TSG-6的保护作用减弱。我们还发现，TLR 2/NF-κ B通路的激活被BMSCs和TSG-6抑制。在BMSC和TSG-6的存在下，退化的NPC中的IL-6和TNF-α的水平降低，并且IL-1 β处理的NPC的增殖增加。此外，在体内实验表明，骨髓间充质干细胞和TSG-6恢复MRI T2加权信号强度，并增加胶原蛋白II和聚集蛋白聚糖在退变髓核（NP）组织的表达。最后，我们的结果表明，BMSCs和TSG-6下调TLR 2/NF-κ B B信号转导，并减少MMP和炎症细胞因子的表达在退化的NP组织。本研究首次证实TLR 2/NF-kappa B通路参与TSG-6的抗IDD治疗作用，为BMSCs治疗IDD提供了新的思路。
Inflammation has been correlated with intervertebral disc degeneration (IDD). Recent evidence suggests that TNF-alpha-stimulated gene 6 protein (TSG-6) secreted by bone marrow mesenchymal stem cells (BMSCs) displays a remarkable ability to inhibit inflammatory processes in a variety of diseases. However, it is unknown whether BMSCs exert their therapeutic effect against IDD by secreting TSG-6. Here we investigated the effects of BMSCs and TSG-6 on IDD and explored the possible underlying mechanisms in vitro and in vivo. We found that BMSCs and TSG-6 reduced the expression of MMP-3 and MMP-13, and increased the expression of collagen II and aggrecan in the IL-1 beta-treated nucleus pulposus cells (NPCs), but the protective effects of BMSCs and TSG-6 were attenuated when TSG-6 expression was silenced. We also found that the activation of the TLR2/NF-kappa B pathway was inhibited by BMSCs and TSG-6. The levels of IL-6 and TNF-alpha in the degenerated NPCs were reduced and the proliferation of IL-1 ss-treated NPCs was increased in the presence of BMSCs and TSG-6. Furthermore, in vivo experiments showed that BMSCs and TSG-6 restored the MRI T2-weighted signal intensity and increased collagen II and aggrecan expression in the degenerated nucleus pulposus (NP) tissues. Finally, our results showed that BMSCs and TSG-6 downregulated the TLR2/NF-kappa B signaling and reduced the expression of MMPs and inflammatory cytokines in the degenerated NP tissues. The present study is the first to demonstrate the involvement of TLR2/NF-kappa B pathway in the potential anti-IDD therapeutic effect of TSG-6, and the results provide new insight into the beneficial effect of BMSCs in the treatment of IDD.