Jianpi qingre tongluo prescription alleviates the senescence-associated secretory phenotype with osteoarthritis by regulating STAG1/TP53/P21 signaling pathway

• Published in: Journal of ethnopharmacology 2025-01, Vol.337 (Pt 3), p.118953, Article 118953
• Main Authors: Zhou, Qiao, Liu, Jian, Qi, Yajun, Hu, Yuedi, Li, Yang, Cong, Chengzhi, Chen, Yiming
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cells, Cultured; Chondrocytes - drug effects; Chondrocytes - metabolism; Drugs, Chinese Herbal - pharmacology; Drugs, Chinese Herbal - therapeutic use; Jianpi qingre tongluo prescription; Male; Osteoarthritis; Osteoarthritis - drug therapy; Osteoarthritis - metabolism; Rats; Rats, Sprague-Dawley; Senescence-Associated Secretory Phenotype - drug effects; Signal Transduction - drug effects; Single-cell sequencing; STAG1; The senescent chondrocyte phenotypes associated; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0378-8741; 1872-7573; 1872-7573
• DOI: 10.1016/j.jep.2024.118953

Jianpi Qingre Chubi prescription primarily consists of a compound formula, also known as Huangqin Qingre Chubi Capsules (HQC), which strengthens the spleen and resolves dampness, clear heat, and collaterals. Long-term clinical use has shown that HQC improves joint swelling and pain in patients with osteoarthritis. Mechanistically, we demonstrated that HQC inhibits inflammatory responses, extracellular matrix degradation, and delays chondrocyte senescence. To determine the bioactivity and mechanism of action of Jianpi Qingre Tongluo prescription (HQC) on osteoarthritis (OA). First, the chondroprotective effects of HQC were assessed using histopathology, immunohistochemical staining and protein blotting in an OA rat model. Additionally, we identified key targets for crucial targets of HQC in OA using the Network Pharmacology and Gene Expression Omnibus (GEO) dataset (GSE98918 and GSE152805). In vitro conditions, IL-1β-treated chondrocytes served to study the impact of HQC on OA development and the senescence-associated secretory phenotype (SASP). This was evaluated using a series of approaches, such as flow cytometry assays, and immunofluorescence staining, and then verified by rescue experiments. Therapy with HQC attenuated the severity of osteoarthritis (demonstrated by histopathology, OARSI grading scores, and Mankin scores) and SASP factors (as indicated by IL-1β, IL-6, IL-4, IL-37, MMP13, ADAMTS5, COL2A1, and ACAN levels, and apoptotic cell death). HQC might treat osteoarthritis via four important targets (STAG1, TP53, P21, and P16), with the p53 signalling pathway representing one of the main pathways. The HQC acts primarily on chondrocyte clusters. In vitro experiments indicated that STAG1 overexpression accelerates chondrocyte apoptosis, promotes SASP factor expression and extracellular matrix (ECM) degradation, and facilitates OA progression. HQC-containing serum suppressed the expression of the STAG1/TP53/P21 pathway, regulated SASP factors, and restored ECM balance. Jianpi Qingre Tongluo prescription modulated SASP factors by regulating the STAG1/TP53/P21 signal transduction axis and decelerating cartilage senescence and degradation in patients with OA. Jianpi Qingre Tongluo may be an effective drug candidate. [Display omitted] .