Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model

• Published in: Arthritis research & therapy 2021-12, Vol.23 (1), p.294-294, Article 294
• Main Authors: Li, Muzhe, Li, Huiyun, Ran, Xun, Yin, Han, Luo, Xuling, Chen, Zhiwei
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviruses; Animals; Arthritis; Care and treatment; Cartilage; Cartilage, Articular; Cytokines; Gene Knockdown Techniques; Gene therapy; Health aspects; Immune system; Immunohistochemistry; Inflammation; Interleukin-1; Interleukin-1 receptor-associated kinase 4; Interleukin-1 Receptor-Associated Kinases - genetics; Knee; Laboratory animals; Methods; Osteoarthritis; Osteoarthritis - genetics; Proteins; Rabbits; Synovial Membrane; Synovitis; Synovitis - genetics; Toll-like receptor/IL-1 receptor; Tumor necrosis factor-TNF
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-021-02684-8

The use of interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor as a treatment for the inflammatory joint disease is a promising method. However, its underlying mechanism in osteoarthritis (OA) remains unclear. The purpose of this study is to look into the effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the OA rabbit model. Ad-shIRAK4 was injected two weeks after anterior cruciate ligament resection. Six weeks later, the rabbits were killed. The expression of IRAK4, TNFR-associated factor 6(TRAF6), TGF-activated kinase 1(TAK1), p-IKB kinase (p-IKK), p-nuclear factor kappa-B (p-NFκB), p38, and p-p38 in the synovial membrane was detected by western blot, qRT-PCR, and immunohistochemistry analysis. Immunohistochemistry was to detect the expression of IRAK4 proteins in articular cartilage. H&E staining was to assess the pathological changes of synovium and cartilage. The levels of interleukin (IL)-1β, tumor necrosis factor-α(TNF-α), and MMP-13 in the synovial fluid were measured by ELISA. X-ray and micro-computerized tomography (μCT) scans were used to assess knee joint conditions and microstructure of subchondral bone. IRAK4 expression levels in synovial tissues of the OA model group exhibited a significant upward trend. Ad-shIRAK4 significantly reduced IRAK4 mRNA expression in synovium tissues. Notably, Ad-shIRAK4 suppressed the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling. In addition, in the Ad-shIRAK4 treatment group, we can see less inflammatory cell infiltration and reduced hyperplasia and angiogenesis. The levels of IL-1β, TNF-α, and MMP-13 in the synovial fluid in the OA model group were significantly higher than that in the control group, which were reduced by Ad-shIRAK4 treatment. Finally, Results of HE stains, immunohistochemistry, and μCT showed that Ad-shIRAK4 treatment has a protective effect on cartilage damage. IRAK4 is significantly upregulated in the synovium from the osteoarthritis rabbit model. In addition, Ad-shIRAK4 reduced the expression of IRAK4 and suppressed TLR/IL-1R signaling in the synovium from the osteoarthritis rabbit model. Ad-shIRAK4 could alleviate synovitis and cartilage degradation in the osteoarthritis rabbit model, and thus alleviate the symptoms of OA and prevent the progression of OA.