Targeting CCNE2 to alleviate rheumatoid arthritis through inducing senescence and apoptosis
Rui Xu1,2, Youhan Mei1,2, Hanrui Liu1,2
1Department of Orthopaedic Surgery, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, China.
Abstract:
This study explored the role of cellular senescence in the progression of rheumatoid arthritis (RA) and evaluated the targeting of Cyclin E2 (CCNE2) in synovial fibroblasts as a potential therapeutic approach. A risk prediction model for RA was developed using LASSO regression analysis, which involved analyzing differential gene expression and performing Gene Set Enrichment Analysis (GSEA). The model was validated using the Receiver Operating Characteristic (ROC) curve. CCNE2 expression was examined via Western blotting. Knockdown of CCNE2 in RA synovial fibroblasts (RASFs) using shRNA resulted in reduced cell viability, increased apoptosis, and elevated levels of senescence markers such as p16, p21, and p53. Additionally, senescence-associated β-galactosidase (SA-β-Gal) activity and H3K9me3 fluorescence intensity were significantly increased. In vivo, Adeno-Associated Virus (AAV)-mediated intra-articular injection of shCCNE2 in a collagen-induced arthritis (CIA) mouse model significantly reduced the arthritis index, alleviated joint inflammation, and suppressed CCNE2 expression. Furthermore, the secretion of SASP factors such as MMP-3 and IL-8 was significantly enhanced. These findings suggest that targeting CCNE2 induces senescence in RASFs and may offer a novel strategy to mitigate RA progression and inflammation.
Insights
This study developed a risk prediction model for rheumatoid arthritis (RA) and found that targeting Cyclin E2 (CCNE2) in fibroblast-like synoviocytes can reduce RA progression and joint inflammation.
Area of Science:
- Rheumatology
- Cellular Biology
- Molecular Medicine
Background:
- Cellular senescence plays a role in rheumatoid arthritis (RA) pathogenesis.
- Identifying biomarkers and therapeutic targets for RA is crucial.
Purpose of the Study:
- To investigate the role of cellular senescence in RA progression.
- To evaluate Cyclin E2 (CCNE2) as a therapeutic target in RA.
- To develop a risk prediction model for RA.
Main Methods:
- Differential gene expression analysis and Gene Set Enrichment Analysis (GSEA).
- LASSO regression for risk model development and ROC curve analysis.
- CCNE2 knockdown in rheumatoid arthritis synovial fibroblasts (RASFs) and in vivo validation in a collagen-induced arthritis (CIA) mouse model.
Main Results:
- A risk prediction model for RA was established (AUC > 0.6).
- CCNE2 expression was significantly increased in RA synovial tissues.
- CCNE2 knockdown in RASFs reduced cell viability, increased apoptosis, and induced senescence markers.
- Targeting CCNE2 in vivo ameliorated arthritis index and joint inflammation in RA mice.
Conclusions:
- A novel risk prediction model for RA has been developed.
- Targeting CCNE2 in synoviocytes is a potential therapeutic strategy for RA.
- Suppression of CCNE2 induces senescence, mitigating RA progression and joint inflammation.
