Melatonin reversed tumor necrosis factor-alpha-inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein
Melatonin reversed tumor necrosis factor-alpha-inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein
复制标题
褪黑素通过稳定 SMAD1 蛋白逆转肿瘤坏死因子-α 抑制的人间充质干细胞成骨作用
DOI：
10.1111/jpi.12349
复制
发表时间：
2016-10-01
影响因子：
10.3
通讯作者：
Huang, Dongsheng
中科院分区：
文献类型：
--
作者：
Lian, Chengjie;Wu, Zizhao;Huang, Dongsheng
肿瘤坏死因子-α（TNF-α）通过促进骨吸收和抑制骨形成在炎症相关的骨质疏松症中起关键作用。已经生产了许多药物通过抑制骨吸收来治疗骨质疏松症，但它们对骨形成几乎没有益处，而骨形成是严重骨丢失患者所需要的。褪黑激素具有抗炎和促成骨作用，有望克服TNF α抑制的成骨作用，值得进一步研究。这项研究表明，褪黑激素挽救了TNF α抑制的人间充质干细胞的成骨作用，并且SMURF 1和SMAD 1之间的相互作用介导了褪黑激素信号传导和TNF α信号传导之间的串扰。此外，褪黑激素治疗被发现下调TNF α诱导的SMURF 1表达，然后减少SMURF 1介导的泛素化和SMAD 1蛋白的降解，导致稳定的骨形态发生蛋白-SMAD 1信号传导活性和TNF α受损的骨生成的恢复。因此，褪黑激素具有调节骨形成、骨吸收和炎症的多方面功能，具有治疗炎症因素引起的骨质疏松症的前景。进一步的研究将集中在揭示褪黑激素下调SMURF 1表达的具体机制，并确认褪黑激素在预防和治疗炎症相关骨丢失中的临床治疗价值。
Tumor necrosis factor-alpha (TNF alpha) plays a pivotal role in inflammation-related osteoporosis through the promotion of bone resorption and suppression of bone formation. Numerous drugs have been produced to treat osteoporosis by inhibiting bone resorption, but they offer few benefits to bone formation, which is what is needed by patients with severe bone loss. Melatonin, which can exert both anti-inflammatory and pro-osteogenic effects, shows promise in overcoming TNF alpha-inhibited osteogenesis and deserves further research. This study demonstrated that melatonin rescued TNFa-inhibited osteogenesis of human mesenchymal stem cells and that the interactions between SMURF1 and SMAD1 mediated the crosstalk between melatonin signaling and TNFa signaling. Additionally, melatonin treatment was found to downregulate TNF alpha-induced SMURF1 expression and then decrease SMURF1-mediated ubiquitination and degradation of SMAD1 protein, leading to steady bone morphogenetic protein-SMAD1 signaling activity and restoration of TNFa-impaired osteogenesis. Thus, melatonin has prospects for treating osteoporosis caused by inflammatory factors due to its multifaceted functions on regulation of bone formation, bone resorption, and inflammation. Further studies will focus on unveiling the specific mechanisms by which melatonin downregulates SMURF1 expression and confirming the clinical therapeutic value of melatonin in the prevention and therapy of bone loss associated with inflammation.