https://orcid.org/0000-0001-6780-6314
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Abstract
Background
Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA.
Methods
The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK‐8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments.
Results
In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1β and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1β-induced chondrocytes and DMM-induced rats.
Conclusion
RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.
Abbreviations
KOA, Knee osteoarthritis; RAR, Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae; TCM, Traditional Chinese medicine; DMM, Destabilization of the medial meniscus model; ROS, Reactive oxygen species; SOD, Superoxide dismutase; GO, Gene ontology; KEGG, Kyoto Encyclopedia of genes and genomes; OA, Osteoarthritis; NSAIDs, Nonsteroidal anti-inflammatory medicines; MAPK, Mitogen-activated protein kinase; TNF-α, Tumor necrosis factor-α; SOX9, SRY-related high mobility group box 9; MMP-13, Matrix metalloproteinase-13; BP, Biological process; CC, Cellular component.
Ethics Statement
All databases in this study are public databases, the contents of which are publicly available and allow unrestricted reuse through open licenses. According to the official document issued by the National Science and Technology Ethics Committee of China, the use of legally obtained public data is not subject to ethical scrutiny (https://www.gov.cn/zhengce/zhengceku/202302/28/content_5743658.htm). Therefore, for this study involving public databases, the need for ethics approval was waived (Ethics Committee of Changchun University of Chinese Medicine). All experimental animals survived at a constant temperature and humidity of 23 °C, with sufficient water and food, and a 12 h light/dark cycle. The pain of the rats was minimized during all surgical procedures. The animal studies were approved by the Animal Ethics Committee of Changchun University of Chinese Medicine (Application Number: 2024218) in accordance with the guidelines of the Guide for the Care and Use of Laboratory Animals.
Acknowledgments
The Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine has provided excellent technical support.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas. The authors participated in drafting, revising or critically reviewing the article. They provided final approval of the version to be published, agreed on the journal to which the article has been submitted, and agreed to be accountable for all aspects of the work. Wenhai Zhao is the first corresponding author, Haisi Dong is the second corresponding author.
Disclosure
The authors report no conflicts of interest in this work.