Abstract
As life expectancy increases, Osteoarthritis (OA) is becoming a more frequently seen chronic joint disease. The main characteristics of OA are loss of articular cartilage, subchondral bone sclerosis, and synovial inflammation. Baicalein (Bai), a traditional Chinese medicine extracted from Scutellaria baicalensis Georgi, has been demonstrated to exert notable anti-inflammatory effects in previous studies, suggesting its potential effect in the treatment of OA. In this study, we first predicted the action targets of Bai, mapped target genes related to OA, identified potential anti-OA targets for Bai, performed gene ontology (GO) enrichment, and KEGG signaling pathway analyses of the action targets, and analyzed the molecular docking of key Bai targets. Additionally, the effect and potential mechanism of Bai against OA were verified in mouse knee OA models induced by destabilized medial meniscus (DMM) surgery. GO and KEGG analyses showed that 19 anti-OA targets were mainly involved in the response to oxidative stress, the response to hypoxia and apoptosis, and the PI3K-Akt and p53 signaling pathways. Molecular docking results indicated that BAX, BCL 2, and Caspase 3 enriched in the apoptotic signaling pathway have high binding affinity with Bai. Validation experiments showed that Bai can significantly attenuate the loss of articular cartilage (OARSI score), suppress synovial inflammation (synovitis score), and ameliorate subchondral bone resorption measured by micro-CT. In addition, Bai notably inhibited the expression of apoptosis-related proteins in articular cartilage (BAX, BCL 2, and Caspase 3). By combining network pharmacology with experimental validation, our study identifies and verifies the importance of the apoptotic signaling pathway in the treatment of OA by Bai. Bai may have promising application and potential therapeutic value in OA treatment.
Highlights
Osteoarthritis (OA) is a severe, debilitating disease that affects the whole joint system and that is characterized by cartilage degeneration, subchondral bone sclerosis, and synovial hypertrophy (Katz et al, 2021)
A total of 37 potential targets of Bai were found based on screening in the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) database, 2085 OA-related targets were extracted from the GeneCards, DrugBank, Targets Database (TTD), PharmGKB, and Online Mendelian Inheritance in Man (OMIM) databases, and a total of 19 anti-OA targets were extracted, including BCL2, CASP3, BAX, and PTGS2 (Figure 1A)
The top 10 significantly enriched terms in the biological processes (BPs), molecular functions (MFs), and cellular components (CCs) categories were selected, and the target proteins were mainly involved in the response to oxidative stress and the response to hypoxia
Summary
Osteoarthritis (OA) is a severe, debilitating disease that affects the whole joint system and that is characterized by cartilage degeneration, subchondral bone sclerosis, and synovial hypertrophy (Katz et al, 2021). Wage losses due to OA amount to $65 billion, and direct medical costs exceed $100 billion (Hawker, 2019). Persons with knee OA spend an average of approximately $15000 (discounted) over their lifetimes on the direct medical costs of OA (Losina et al, 2015). Despite these staggering statistics, FDA-approved therapies for OA remain limited, and no diseasemodifying osteoarthritis drugs (DMOADs) can prevent or restrain the development of OA (Grandi and Bhutani, 2020). Pharmacologic inhibitors of apoptosis may provide a novel treatment option for OA patients
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