Long Ling, Luo Hao, Wang Yi, Gu Jiaxiang, Xiong Jiachao, Tang Xiaokai, Lv Hao, Zhou Faxin, Cao Kai, Lin Sijian
Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, 332000, Jiangxi, China.
Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep;397(9):7071-7087. doi: 10.1007/s00210-024-03100-z. Epub 2024 Apr 21.
Inflammation-induced osteoclast proliferation is a crucial contributor to impaired bone metabolism. Kurarinone (KR), a flavonoid extracted from the Radix Sophorae Flavescentis, exhibits notable anti-inflammatory properties. Nevertheless, the precise influence of KR on osteoclast formation remains unclear. This study's objective was to assess the impact of KR on osteoclast activity in vitro and unravel its underlying mechanism. Initially, a target network for KR-osteoclastogenesis-osteoporosis was constructed using network pharmacology. Subsequently, the intersecting targets were identified through the Venny platform and a PPI network was created using Cytoscape 3.9.1. Key targets within the network were identified employing topological algorithms. GO enrichment and KEGG pathway analysis were then performed on these targets to explore their specific functions and pathways. Additionally, molecular docking of potential core targets of KR was conducted, and the results were validated through cell experiments. A total of 83 target genes overlapped between KR and osteoclastogenesis-osteoporosis targets. Enrichment analysis revealed their role in inflammatory response, protein tyrosine kinase activity, osteoclast differentiation, and MAPK and NF-κB signaling pathways. PPI analysis and molecular docking demonstrate that key targets MAPK14 and MAPK8 exhibit more stable binding with KR compared to other proteins. In vitro experiments demonstrate that KR effectively inhibits osteoclast differentiation and bone resorption without cellular toxicity. It suppresses key osteoclast genes (NFATc1, c-Fos, TRAP, MMP9, Ctsk, Atp6v2), hinders IκB-α degradation, and inhibits ERK and JNK phosphorylation, while not affecting p38 phosphorylation. The results indicate that KR may inhibit osteoclast maturation and bone resorption by blocking NF-κB and MAPK signaling pathways, suggesting its potential as a natural therapeutic agent for osteoporosis.
炎症诱导的破骨细胞增殖是骨代谢受损的关键因素。苦参酮（KR）是从苦参中提取的一种黄酮类化合物，具有显著的抗炎特性。然而，KR对破骨细胞形成的确切影响仍不清楚。本研究的目的是评估KR在体外对破骨细胞活性的影响，并揭示其潜在机制。首先，利用网络药理学构建了KR-破骨细胞生成-骨质疏松症的靶点网络。随后，通过Venny平台确定了交集靶点，并使用Cytoscape 3.9.1创建了蛋白质-蛋白质相互作用（PPI）网络。采用拓扑算法确定网络中的关键靶点。然后对这些靶点进行基因本体（GO）富集和京都基因与基因组百科全书（KEGG）通路分析以探索其具体功能和通路。此外，对KR的潜在核心靶点进行了分子对接，并通过细胞实验验证了结果。KR与破骨细胞生成-骨质疏松症靶点之间共有83个重叠的靶基因。富集分析揭示了它们在炎症反应、蛋白酪氨酸激酶活性、破骨细胞分化以及丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路中的作用。PPI分析和分子对接表明，与其他蛋白质相比，关键靶点丝裂原活化蛋白激酶14（MAPK14）和丝裂原活化蛋白激酶8（MAPK8）与KR的结合更稳定。体外实验表明，KR可有效抑制破骨细胞分化和骨吸收，且无细胞毒性。它抑制关键的破骨细胞基因（活化T细胞核因子1（NFATc1）、原癌基因c-Fos、抗酒石酸酸性磷酸酶（TRAP）、基质金属蛋白酶9（MMP9）、组织蛋白酶K（Ctsk）、ATP酶V型质子转运体2（Atp6v2）），阻碍IκB-α降解，并抑制细胞外信号调节激酶（ERK）和应激活化蛋白激酶（JNK）磷酸化，而不影响p38磷酸化。结果表明，KR可能通过阻断NF-κB和MAPK信号通路抑制破骨细胞成熟和骨吸收，提示其作为骨质疏松症天然治疗剂的潜力。
