Spermidine activates RIP1 deubiquitination to inhibit TNF-α-induced NF-κB/p65 signaling pathway in osteoarthritis

Abstract

Spermidine has been known to inhibit the production of pro-inflammatory cytokines. However, there are no reports about anti-inflammatory effects of spermidine on osteoarthritis (OA). Herein, we examined whether OA progression could be delayed by intraperitoneal injection (i.p.) of spermidine in the anterior cruciate ligament transection (ACLT) and TNF-α induced arthritis (TIA) mouse models. During the process, human FLS cells (H-FLS) were used to investigate the potential ubiquitination mechanism of spermidine-mediated RIP1 in TNF-α-induced NF-κB/p65 signaling. We found that spermidine attenuated synovitis, cartilage degeneration and osteophyte formation, resulting in substantially lower OARSI scores and TNF-α scores in spermidine-treated ACLT and TIA mice. In terms of the mechanism, 9 μM spermidine did not affect the viability, proliferation, cell cycle and apoptosis of H-FLS, and exerted inhibitory effects by activating CYLD-mediated RIP1 deubiquitination on TNF-α-induced NF-κB/p65 signaling in H-FLS. From these data, we can conclude that spermidine attenuates OA progression by the inhibition of TNF-α-induced NF-κB pathway via the deubiquitination of RIP1 in FLS. Therefore, intake of spermidine could be a potential therapy for preventing OA.

Monocytes, Macrophages and Joint Inflammation in Osteoarthritis

“…ACLT in mice has been shown to cause synovitis, a study by Chen et al showed a significant increase in synovitis score, as measure quantitatively [47], as well as increased cell infiltration and intra-articular synovial hyperplasia and abundant cell infiltration 8 weeks post-surgery [48]. Furthermore, these mice show a significant increase in pro-inflammatory cytokines, TNFα and IL-6, in the serum of the ACLT mice compared to sham control.…”

Weighted gene co-expression network analysis reveals specific modules and hub genes related to immune infiltration of osteoarthritis

“…Meanwhile, based on functional enrichment via GSVA in this study, it was suggested that TNF-α signaling via NF-κB and the ROS pathway play important roles in the progression of OA, which has been confirmed in other studies. Chen et al found that spermine can reduce the progression of OA by inhibiting the TNF-α/ NF-κB pathway (29). It has also been reported that TNF-α plays a major pathological role in rheumatoid arthritis (RA) via NF-κB and the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway (30).…”

New Insights into the Roles and Mechanisms of Spermidine in Aging and Age-Related Diseases

“…hypothesized that spermidine is a potential therapy for osteoarthritis because it activates autophagy in osteoarthritic cartilage and reverses the reduction in polyamine synthesis [ 136 ]. Chen et al showed that spermidine alleviates synovitis, osteophyte formation, and cartilage degeneration by inhibiting TNF-α induced NF-κB/p65 signaling pathway in osteoarthritis [ 137 ]. In addition, spermidine was shown to exhibit antioxidant, anti-inflammatory, and chondroprotective roles in osteoarthritic chondrocytes [ 138 ].…”