Guo Song, Su Qihang, Wen Junxiang, Zhu Kai, Tan Jun, Fu Qiang, Sun Guixin
Department of Orthopaedics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
J Cell Mol Med. 2021 May;25(10):4709-4720. doi: 10.1111/jcmm.16424. Epub 2021 Mar 18.
Oxidative stress in the lumbar disc leads to the degeneration of nucleus pulposus (NP). However, the molecular mechanisms underlying this process remain unclear. In this study, we delineated a key calcium-binding protein, S100A9, which was induced by oxidative stress and was highly expressed in the degenerative NP. Immunofluorescence staining and Western blotting revealed that S100A9 induced NP cell apoptosis in vitro by up-regulating the expression of pro-apoptotic markers, including cleaved caspase-3, cytochrome c and Bax. Moreover, RT-PCR analyses revealed that the expression of S100A9 caused NP matrix degradation by up-regulating the expression of matrix degradation enzymes and increased the inflammatory response by up-regulating cytokine expression. Therefore, S100A9 induced NP cell degeneration by exerting pro-apoptotic, pro-degradation and pro-inflammatory effects. The detailed mechanism underlying S100A9-induced NP degeneration was explored by administering SC75741, a specific NF-κB inhibitor in vitro. We concluded that S100A9 induced NP cell apoptosis, caused matrix degradation and amplified the inflammatory response through the activation of the NF-κB signalling pathway. Inhibition of these pro-apoptotic, pro-degradation and pro-inflammatory effects induced by S100A9 in NP may be a favourable therapeutic strategy to slow lumbar disc degeneration.
腰椎间盘的氧化应激会导致髓核（NP）退变。然而，这一过程背后的分子机制仍不清楚。在本研究中，我们确定了一种关键的钙结合蛋白S100A9，它由氧化应激诱导，在退变的NP中高表达。免疫荧光染色和蛋白质印迹分析显示，S100A9在体外通过上调促凋亡标志物（包括裂解的半胱天冬酶-3、细胞色素c和Bax）的表达诱导NP细胞凋亡。此外，逆转录-聚合酶链反应（RT-PCR）分析显示，S100A9的表达通过上调基质降解酶的表达导致NP基质降解，并通过上调细胞因子表达增强炎症反应。因此，S100A9通过发挥促凋亡、促降解和促炎作用诱导NP细胞退变。通过在体外给予特异性NF-κB抑制剂SC75741，探索了S100A9诱导NP退变的详细机制。我们得出结论，S100A9通过激活NF-κB信号通路诱导NP细胞凋亡、导致基质降解并放大炎症反应。抑制S100A9在NP中诱导的这些促凋亡、促降解和促炎作用可能是减缓腰椎间盘退变的一种有利治疗策略。
