Melatonin up-regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2-inactivated NF-kappa B pathway
Melatonin up-regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2-inactivated NF-kappa B pathway
复制标题
褪黑素通过上调 BMMSCs 成骨能力来拯救骨质疏松症，但通过 MT2 失活的 NF-B 途径抑制 BMMSC 介导的破骨细胞生成
DOI：
10.1111/bph.14972
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Wang Huiming
中科院分区：
文献类型：
--
作者：
Zhou Yi;Wang Chaowei;Si Jinyan;Wang Baixiang;Zhang Denghui;Ding Ding;Zhang Jian;Wang Huiming
背景与目的褪黑激素是一种参与骨稳态的神经激素。褪黑素（Melatonin，MT）是一种重要的骨代谢调节因子，可调控骨的形成和吸收，而骨髓间充质干细胞（bone marrow mesenchymal stem cells，BMMSCs）在MT介导的骨形成和吸收中的作用尚不明确。敲除褪黑素受体，研究NF-κB信号通路和NF-κB配体受体激活因子（RANKL）表达。通过直接接触或间接接触系统检测骨髓间充质干细胞和破骨细胞之间的通讯。Key ResultsBone loss and microstructure disorder in mice was reversed after melatonin treatment，as a result of anabolic and anti-resorption effects.在体外，生理（低）浓度的褪黑激素促进骨髓间充质干细胞，成骨谱系的承诺和细胞外矿化，但对细胞外基质的合成没有影响。MT基因敲除后，尤其是MT 2基因敲除后，褪黑素对成骨的促进作用减弱。经典的NF-κB信号通路是MT受体激活后第一个发现的下游信号通路，并且发现在骨生成过程中被褪黑素下调。褪黑素通过抑制骨髓间充质干细胞产生RANKL抑制骨髓间充质干细胞介导的破骨细胞生成，这种作用仅在骨髓间充质干细胞和破骨细胞前体细胞以间接接触方式共培养时发生。结论和意义我们的工作表明，褪黑素在骨平衡中起着至关重要的作用，通过抑制MT 2依赖的NF-κB信号通路显著加速骨髓间充质干细胞的成骨分化，并通过RANKL旁分泌下调破骨细胞生成。
Background and PurposeMelatonin is a neurohormone involved in bone homeostasis. Melatonin directs bone remodelling and the role of bone marrow mesenchymal stem cells (BMMSCs) in the regulating melatonin‐mediated bone formation–resorption balance remains undefined.Experimental ApproachOsteoporosis models were established and bone tissue and serum were collected to test the effects of melatonin on bone homeostasis. Melatonin receptors were knocked down, the NF‐κB signalling pathway and receptor activator of NF‐κB ligand (RANKL) expression were investigated. Communication between bone marrow mesenchymal stem cells and osteoclasts was detected with direct‐contact or indirect‐contact system.Key ResultsBone loss and microstructure disorder in mice were reversed after melatonin treatment, as a result of anabolic and anti‐resorptive effects. In vitro, a physiological (low) concentration of melatonin promoted the bone marrow mesenchymal stem cells, osteogenic lineage commitment and extracellular mineralization but had no impact on extracellular matrix synthesis. After MT knockdown, especially MT2, the positive effects of melatonin on osteogenesis were attenuated. The canonical NF‐κB signalling pathway was the first discovered downstream signalling pathway after MT receptor activation and was found to be down‐regulated by melatonin during osteogenesis. Melatonin suppressed BMMSC‐mediated osteoclastogenesis by inhibiting RANKL production in BMMSCs and this effect only occurred when BMMSCs and osteoclast precursors were co‐cultured in an indirect‐contact manner.Conclusion and ImplicationsOur work suggests that melatonin plays a crucial role in bone balance, significantly accelerates the osteogenic differentiation of bone marrow mesenchymal stem cells by suppressing the MT2‐dependent NF‐κB signalling pathway, and down‐regulates osteoclastogenesis via RANKL paracrine secretion.