NF-κB inhibits osteogenic differentiation of mesenchymal stem cells by promoting β-catenin degradation
NF-κB inhibits osteogenic differentiation of mesenchymal stem cells by promoting β-catenin degradation
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DOI：
10.1073/pnas.1300532110
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发表时间：
2013-06-04
影响因子：
11.1
通讯作者：
Wang, Cun-Yu
中科院分区：
文献类型：
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作者：
Chang, Jia;Liu, Fei;Wang, Cun-Yu
间充质干细胞（MSC）为基础的移植是一种有前途的治疗方法，骨再生和修复。在治疗性骨再生领域中，缺损或损伤组织经常因炎性介质的异常表达而发炎。越来越多的证据表明，促炎细胞因子抑制成骨分化和骨形成。因此，对于成功的MSC介导的修复，重要的是克服炎症介导的组织再生抑制。在这项研究中，使用遗传学和化学方法，我们发现，促炎细胞因子TNF和IL-17刺激I κ B激酶（IKK）-NF-κ B和受损的成骨分化的MSC。相反，抑制IKK-NF-κ B可显著增强MSC介导的骨形成。从机制上讲，我们发现IKK-NF-κ B活化通过诱导Smurf 1和Smurf 2促进β-连环蛋白泛素化和降解。为了将我们的基本发现转化为潜在的临床应用，我们发现IKK小分子抑制剂IKKVI增强了MSC的成骨分化。更重要的是，IKKVI的递送促进了体内MSC介导的颅面骨再生和修复。考虑到NF-κ B在炎症和感染中的作用，我们的研究结果表明，靶向IKK-NF-κ B可能在增强骨再生和修复以及抑制炎症方面具有双重益处，并且这个概念也可能适用于许多其他组织再生情况。
Mesenchymal stem cell (MSC)-based transplantation is a promising therapeutic approach for bone regeneration and repair. In the realm of therapeutic bone regeneration, the defect or injured tissues are frequently inflamed with an abnormal expression of inflammatory mediators. Growing evidence suggests that proinflammatory cytokines inhibit osteogenic differentiation and bone formation. Thus, for successful MSC-mediated repair, it is important to overcome the inflammation-mediated inhibition of tissue regeneration. In this study, using genetic and chemical approaches, we found that proinflammatory cytokines TNF and IL-17 stimulated I kappa B kinase (IKK)-NF-kappa B and impaired osteogenic differentiation of MSCs. In contrast, the inhibition of IKK-NF-kappa B significantly enhanced MSC-mediated bone formation. Mechanistically, we found that IKK-NF-kappa B activation promoted beta-catenin ubiquitination and degradation through induction of Smurf1 and Smurf2. To translate our basic findings to potential clinic applications, we showed that the IKK small molecule inhibitor, IKKVI, enhanced osteogenic differentiation of MSCs. More importantly, the delivery of IKKVI promoted MSC-mediated craniofacial bone regeneration and repair in vivo. Considering the well established role of NF-kappa B in inflammation and infection, our results suggest that targeting IKK-NF-kappa B may have dual benefits in enhancing bone regeneration and repair and inhibiting inflammation, and this concept may also have applicability in many other tissue regeneration situations.