Abstract：
BACKGROUND: Preventing joint edema is crucial in halting osteoarthritis (OA) progression. Growing clinical evidence indicate that Jianpi-Tongluo Formula (JTF) may have a promising anti-edema effect. However, the therapeutic properties of JTF and the underlying mechanisms remains unclear.
METHODS: An OA rat model was established and employed to evaluate pharmacological effects of JTF in vivo based on dynamic histopathologic assessments and micro-CT observations. Then, OA-related genes and potential targets of JTF were identified through clinical transcriptomic data analysis and \"disease gene-drug target\" network analysis, which were verified by a series of in vivo experiments.
RESULTS: JTF administration effectively reduced pain and joint edema, inhibited matrix degradation, chondrocyte apoptosis, and aquaporin expression in OA rats. Notably, JTF dose-dependently reversed damage-associated molecular patterns and inflammatory factor upregulation. Mechanically, our \"disease gene-drug target\" network analysis indicated that the NCOA4-HMGB1-GSK3B-AQPs axis, implicated in ferroptosis and aquaporin dysregulation, may be potentially served as a target of JTF against OA. Accordingly, JTF mitigated NCOA4, HMGB1, and GSK3B expression, oxidative stress, and iron metabolism aberrations in OA rats. Furthermore, JTF treatment significantly attenuated the aberrant upregulation of AQP1, AQP3, and AQP4 proteins observed in cartilage tissues of OA rats.
CONCLUSIONS: Our data reveal for the first time that JTF may exert cartilage protective and anti-edema effects in osteoarthritis therapy by inhibiting NCOA4-HMGB1-driven ferroptosis and aquaporin dysregulation.
METHODS: An OA rat model was established and employed to evaluate pharmacological effects of JTF in vivo based on dynamic histopathologic assessments and micro-CT observations. Then, OA-related genes and potential targets of JTF were identified through clinical transcriptomic data analysis and \"disease gene-drug target\" network analysis, which were verified by a series of in vivo experiments.
RESULTS: JTF administration effectively reduced pain and joint edema, inhibited matrix degradation, chondrocyte apoptosis, and aquaporin expression in OA rats. Notably, JTF dose-dependently reversed damage-associated molecular patterns and inflammatory factor upregulation. Mechanically, our \"disease gene-drug target\" network analysis indicated that the NCOA4-HMGB1-GSK3B-AQPs axis, implicated in ferroptosis and aquaporin dysregulation, may be potentially served as a target of JTF against OA. Accordingly, JTF mitigated NCOA4, HMGB1, and GSK3B expression, oxidative stress, and iron metabolism aberrations in OA rats. Furthermore, JTF treatment significantly attenuated the aberrant upregulation of AQP1, AQP3, and AQP4 proteins observed in cartilage tissues of OA rats.
CONCLUSIONS: Our data reveal for the first time that JTF may exert cartilage protective and anti-edema effects in osteoarthritis therapy by inhibiting NCOA4-HMGB1-driven ferroptosis and aquaporin dysregulation.
摘要：
背景：预防关节水肿对于阻止骨关节炎（OA）进展至关重要。越来越多的临床证据表明，健脾通络方（JTF）可能具有有希望的抗水肿作用。然而,JTF的治疗特性和潜在机制尚不清楚.
方法：根据动态组织病理学评估和显微CT观察，建立了OA大鼠模型并用于评估JTF的体内药理作用。然后，通过临床转录组数据分析和“疾病基因-药物靶标”网络分析，确定了OA相关基因和JTF的潜在靶标，通过一系列体内实验验证。
结果：JTF能有效减轻疼痛和关节水肿，抑制基质降解，软骨细胞凋亡,OA大鼠水通道蛋白的表达。值得注意的是,JTF剂量依赖性逆转损伤相关分子模式和炎症因子上调。机械上,我们的“疾病基因-药物靶标”网络分析表明，NCOA4-HMGB1-GSK3B-AQPs轴，与铁凋亡和水通道蛋白失调有关，可能作为JTF对抗OA的目标。因此，JTF减轻了NCOA4、HMGB1和GSK3B的表达，氧化应激，和OA大鼠的铁代谢异常。此外，JTF处理显著减弱OA大鼠软骨组织中观察到的AQP1、AQP3和AQP4蛋白的异常上调。
结论：我们的数据首次揭示了JTF可能通过抑制NCOA4-HMGB1驱动的铁蛋白凋亡和水通道蛋白失调在骨关节炎治疗中发挥软骨保护和抗水肿作用。
方法：根据动态组织病理学评估和显微CT观察，建立了OA大鼠模型并用于评估JTF的体内药理作用。然后，通过临床转录组数据分析和“疾病基因-药物靶标”网络分析，确定了OA相关基因和JTF的潜在靶标，通过一系列体内实验验证。
结果：JTF能有效减轻疼痛和关节水肿，抑制基质降解，软骨细胞凋亡,OA大鼠水通道蛋白的表达。值得注意的是,JTF剂量依赖性逆转损伤相关分子模式和炎症因子上调。机械上,我们的“疾病基因-药物靶标”网络分析表明，NCOA4-HMGB1-GSK3B-AQPs轴，与铁凋亡和水通道蛋白失调有关，可能作为JTF对抗OA的目标。因此，JTF减轻了NCOA4、HMGB1和GSK3B的表达，氧化应激，和OA大鼠的铁代谢异常。此外，JTF处理显著减弱OA大鼠软骨组织中观察到的AQP1、AQP3和AQP4蛋白的异常上调。
结论：我们的数据首次揭示了JTF可能通过抑制NCOA4-HMGB1驱动的铁蛋白凋亡和水通道蛋白失调在骨关节炎治疗中发挥软骨保护和抗水肿作用。
