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

Abstract

Background 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. Methods 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. Results 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. Conclusions 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. Graphical abstract

STS loaded PCL-MECM based hydrogel hybrid scaffolds promote meniscal regeneration via modulating macrophage phenotype polarization

“…In osteoarthritis, the expression of IRAK4 and TRAF6 was dramatically enhanced in the synovium and cartilage. 34 In our study, IL-1β markedly induced the phosphorylation of ERK, p38, JNK, and p65. However, these changes could be restored by STS.…”

“…TRAF6 then stimulates the MAPK and NF-κB signaling pathways. 34 In osteoarthritis induced by meniscus damage, the MAPK and NF-κB pathways are important. NF-κB plays a critical role in the regulation of several genes involved in the inflammatory response and cell death control.…”

IRAK4 inhibition: an effective strategy for immunomodulating peri-implant osseointegration via reciprocally-shifted polarization in the monocyte-macrophage lineage cells

“…MyD88 signaling regulates the network of the innate immune system, IL-1 ligand sensing, and osteoclast formation [19,32]. IRAK4 is signi cantly up-regulated in the synovium of osteoarthritis, and Ad-shIRAK4 decreased its expression via inhibiting the TLR/IL-1R signaling pathway and alleviated synovitis and cartilage degeneration [33]. Moreover, IRAK4 kinase activity controls the activation of IRF5 which contributes to macrophage polarization.…”

IRAK4 inhibition: an effective strategy for immunomodulating peri-implant osseointegration via reciprocally-shifted polarization in the monocyte-macrophage lineage cells

“…MyD88 signaling regulates the network of the innate immune system, IL-1 ligand sensing, and osteoclast formation [ 19 , 32 ]. IRAK4 is significantly up-regulated in the synovium of osteoarthritis, and Ad-shIRAK4 decreased its expression via inhibiting the TLR/IL-1R signaling pathway and alleviated synovitis and cartilage degeneration [ 33 ]. Moreover, IRAK4 kinase activity controls the activation of IRF5 which contributes to macrophage polarization.…”