九里香酮通过调控C-EBP/β抑制老年性骨关节炎软骨基质降解的分子机制

Extracellular matrix (ECM) degradation mediated by matrix metalloproteinase-13 (MMP-13) plays an important role in the pathogenesis of aging osteoarthritis (OA). GSK-3β phosphorylated C/EBPβ is essential for the activity of NF-κB signaling pathway, which promotes the expression of MMP-13. However, the underlying mechanism is still unclear. Our previous study showed that 5,7,3’,4’-tetramethoxyflavone (TMF) exhibited protective activity for cartilage through inhibition of GSK-3β and C/EBPβ activity. In this study, we will investigate the molecular mechanism of C/EBPβ in up regulating MMP-13 expression through mediating NF-κB signaling pathway in vivo and in vitro. These will be verified in C/EBPβ knockout mice. TMF can attenuate the degradation of ECM through inhibiting the activity of C/EBPβ and down regulating the expression of MMP-13. This study could provide new foundation for investigation the molecular mechanism in apoptosis in OA chondrocytes, new target, and new potential medicine. It also could provide new scientific theory for exploring the modernization development of Traditional Chinese Medicine Murraya Exotica (L.).

MMP-13调控的软骨基质降解在老年性骨关节炎发病机制中具有重要的作用。GSK-3β磷酸化的C/EBPβ是NF-κB信号通路表达所必需的因子，而NF-κB可促进MMP-13的表达，但具体的分子机制还不是很清楚。本课题前期研究基础发现，九里香酮（TMF）可抑制GSK-3β活性，抑制C/EBPβ的表达，保护关节软骨。本课题拟从体内、体外研究C/EBPβ通过调控NF-κB信号通路而上调表达MMP-13的分子机制，进一步利用C/EBPβ-/-小鼠证实该机制。TMF可抑制C/EBPβ活性，抑制MMP-13表达，进而抑制关节软骨基质降解。本课题可为深入研究OA软骨细胞凋亡机制、寻找新靶点、开发新药奠定基础，也为中药九里香现代化开发提供有益的科学依据。

在老年性骨关节炎发病机制中，MMP-13调控软骨基质降解发挥着重要的作用。磷酸化的C/EBPβ是NF-κB信号通路表达所必需的因子，而NF-κB可促进MMP-13的表达，但具体的分子机制还不是很清楚。本课题前期研究基础发现，九里香酮（TMF）可抑制GSK-3β活性，抑制C/EBPβ的表达，保护关节软骨。. 本课题从体内研究证实TMF可有效抑制OA大鼠的软骨退化。体外研究发现IL-1β可诱导刺激软骨细胞引起C/EBPβ、MMP-13和p65表达水平升高，NRF2和Col2a1的表达水平下降；而TMF可回调该趋势。TMF可同时抑制miR-34a的表达，进而显著抑制miR-34a过表达而引起的软骨细胞凋亡。C/EBPβ通过上调miR-34a，抑制SIRT1表达，促进MMP-13活性表达，其中的分子机制可能与C/EBPβ激活NF-κB信号通路有关。C/EBPβ上调MMP-13的表达呈氧化依赖性。NRF2通过抑制C/EBPβ的表达从而调控NF-κB信号通路，而TMF可通过激活PI3K/AKT信号通路、SIRT1等的表达抑制C/EBPβ的活性。. 综上，C/EBPβ通过调控NF-κB信号通路而上调MMP-13的表达，而TMF可抑制C/EBPβ活性，抑制MMP-13表达，进而抑制关节软骨基质降解。本课题可为深入研究OA软骨细胞凋亡机制、寻找新靶点、开发新药奠定基础，也为中药九里香现代化开发提供有益的科学依据。