Melatonin rescued interleukin 1β-impaired chondrogenesis of human mesenchymal stem cells.
Melatonin rescued interleukin 1β-impaired chondrogenesis of human mesenchymal stem cells.
复制标题
褪黑激素拯救白细胞介素1β受损的人间充质干细胞软骨形成
DOI：
10.1186/s13287-018-0892-3
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发表时间：
2018-06-14
影响因子：
7.5
通讯作者：
Huang D
中科院分区：
文献类型：
--
作者：
Gao B;Gao W;Wu Z;Zhou T;Qiu X;Wang X;Lian C;Peng Y;Liang A;Qiu J;Zhu Y;Xu C;Li Y;Su P;Huang D
骨关节炎（OA）是一种广泛的关节炎疾病，也是导致残疾的主要原因。越来越多的证据表明，炎症在其发病机制中起着关键作用。白细胞介素-1 β（IL-1β）是OA局部炎症过程的主要介质。目前OA的治疗主要集中在疾病晚期的症状。利用骨髓间充质干细胞（BMSC）再生软骨是一种有吸引力的方法，但在OA的情况下，需要在发炎的环境中进行软骨形成。我们前期的研究表明褪黑素（melatonin，MLT）可以促进骨髓间充质干细胞向软骨细胞分化，但MLT是否能够挽救IL-1β损伤的人BMSCs向软骨细胞分化尚未确定。MLT具有抗炎和促软骨形成作用，已证明其有潜力击败IL-1β诱导的软骨形成抑制，应进行进一步研究。人骨髓来源的MSC的分离和培养的基础上，我们的系统，已经记录。高密度微团培养系统用于人BMSC的软骨形成分化，这也是先前描述的。用IL-1β和MLT处理人BMSCs诱导软骨形成7、14和21天。然后通过形态学、细胞外基质积累以及软骨形成、代谢和凋亡标记物表达来评价培养的软骨颗粒。TUNEL法检测细胞凋亡。在BMSCs向软骨细胞分化的第21天检测NF-κB通路活性的P65和IκBα磷酸化水平。目前的评估表明，MLT可以从不同方面挽救IL-1β损伤的人BMSCs软骨形成。首先，MLT可以恢复软骨形成颗粒的大小，并拯救基质的合成和积累。其次，MLT可以在mRNA和蛋白水平上调软骨形成标志物COL 2A 1的表达，并且在IL-1β存在下还调节其他软骨形成标志物如ACAN、SOX 9和COL 10A 1的表达水平。第三，MLT可以通过抑制分解代谢基因如MMP、MMP 13和ADAMTS 4的表达来维持软骨形成过程的代谢平衡。MLT可抑制IL-1β诱导的BMSCs细胞凋亡。同时，MLT可抑制IL-1β诱导的NF-κBα和P65的磷酸化水平，提示MLT可抑制IL-1β诱导的NF-κB α的活化。目前的评估表明，MLT可以通过恢复颗粒大小和基质积累，维持代谢平衡，减少细胞凋亡，挽救IL-1β受损的人BMSCs软骨形成。我们的研究还表明，MLT可以减弱IL-1β诱导的NF-κB信号通路的激活，NF-κB信号通路是IL-1β下游最重要的通路，在炎症、凋亡和代谢中起着至关重要的作用。因此，MLT由于其多方面的功能，如减轻炎症，维持代谢平衡和减轻细胞凋亡，具有治疗OA的前景。
Osteoarthritis (OA) is a widespread arthritic disease and a primary cause of disability. Increasing evidence suggests that inflammation has a pivotal part in its pathogenesis. Interleukin-1β (IL-1β) is a primary mediator of local inflammatory processes in OA. Current therapies for OA mainly focus on the symptoms of the advanced stage of the disease. The possible utilization of bone marrow mesenchymal stem cells (BMSCs) to regenerate cartilage is an appealing method, but in the case of OA requires chondrogenesis to take place within an inflamed environment. Our previous study showed that melatonin (MLT) can promote chondrogenic differentiation of MSCs, but whether MLT can rescue IL-1β-impaired chondrogenesis in human BMSCs has not yet been established. MLT, which can have anti-inflammatory and prochondrogenic effects, has demonstrated potential in defeating IL-1β-induced inhibition of chondrogenesis and further study should be conducted. Human bone marrow-derived MSCs were separated and cultured based on our system that was already documented. A high-density micromass culture system was used for the chondrogenic differentiation of human BMSCs, which was also described previously. Human BMSCs were induced for chondrogenesis for 7, 14, and 21 days with the treatment of IL-1β and MLT. The cultured cartilage pellets were then evaluated by morphology, extracellular matrix accumulation, and chondrogenic, metabolic, and apoptotic marker expression. Furthermore, cell apoptosis was assessed by TUNEL assay. The phosphorylation level P65 and IκBα of the NF-κB pathway activity was explored on day 21 of chondrogenic differentiation of BMSCs. The current evaluation showed that MLT can save IL-1β-impaired chondrogenesis of human BMSCs in different aspects. Firstly, MLT can restore the chondrogenic pellet size, and rescue matrix synthesis and accumulation. Secondly, MLT can upregulate chondrogenic marker COL2A1 expression at both mRNA and protein levels, and also regulate the expression levels of other chondrogenic markers like ACAN, SOX9, and COL10A1 in the presence of IL-1β. Thirdly, MLT can maintain the metabolic balance of the chondrogenic process by suppressing expression of catabolic genes, such as MMP, MMP13, and ADAMTS4. Furthermore, MLT can subdue IL-1β-induced cell apoptosis of BMSCs throughout chondrogenesis. Meanwhile, MLT suppressed the phosphorylation level of P65 and IκBα, which were elevated by IL-1β treatment, indicating that MLT can attenuate the IL-1β-induced activation of NF-κB signaling. The current evaluation showed that MLT can save IL-1β-impaired chondrogenesis of human BMSCs by restoring the pellet size and matrix accumulation, and maintaining the metabolic balance, reducing cell apoptosis. Our study also showed that MLT can attenuate the IL-1β-induced activation of the NF-κB signaling pathway, which is the most important pathway downstream of IL-1β, and plays a crucial role in inflammation, apoptosis, and metabolism. Thus, MLT has prospects for treating OA due to its multifaceted functions, such as mitigating inflammation, maintaining metabolic balance, and mitigating apoptosis.
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DOI：
10.1155/2012/741582
发表时间：
2012
期刊：
Arthritis
影响因子：
--
作者：
Rainbow R;Ren W;Zeng L
通讯作者：
Zeng L
影响因子：
4.9
作者：
Cohen SB;Proudman S;Kivitz AJ;Burch FX;Donohue JP;Burstein D;Sun YN;Banfield C;Vincent MS;Ni L;Zack DJ
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Zack DJ
影响因子：
10.3
作者：
Borin TF;Arbab AS;Gelaleti GB;Ferreira LC;Moschetta MG;Jardim-Perassi BV;Iskander AS;Varma NR;Shankar A;Coimbra VB;Fabri VA;de Oliveira JG;Zuccari DA
通讯作者：
Zuccari DA
影响因子：
--
作者：
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通讯作者：
Wolfe, Frederick
DOI：
10.1038/nrrheum.2016.136
发表时间：
2016-10
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
Robinson WH;Lepus CM;Wang Q;Raghu H;Mao R;Lindstrom TM;Sokolove J
通讯作者：
Sokolove J