Salubrinal Alleviates Collagen-Induced Arthritis through Promoting P65 Degradation in Osteoclastogenesis
Ziyu Wang1, Zijian Li1, Guojue Wang1
1Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder that primarily involves joints, further affects the life quality of patients, and has increased mortality. The pathogenesis of RA involves multiple pathways, resulting in some patients showing resistance to the existing drugs. Salubrinal is a small molecule compound that has recently been shown to exert multiple beneficial effects on bone tissue. However, the effect of Salubrinal in RA has not been clearly confirmed. Hence, we induced collagen-induced arthritis (CIA) in DBA/1J mice and found that Salubrinal treatment decreased the clinical score of CIA mice, inhibiting joint damage and bone destruction. Furthermore, Salubrinal treatment downregulated osteoclast number in knee joint of CIA in mice, and suppressed bone marrow-derived osteoclast formation and function, downregulated osteoclast-related gene expression. Moreover, Salubrinal treatment inhibited RANKL-induced NF-κB signaling pathway, and promoted P65 degradation through the ubiquitin-proteasome system, further restrained RANKL-induced osteoclastogenesis. This study explains the mechanism by which Salubrinal ameliorates arthritis of CIA in mice, indicating that Salubrinal may be a potential drug for RA, and expands the potential uses of Salubrinal in the treatment of bone destruction-related diseases.
Insights
Salubrinal treatment reduced joint damage and bone destruction in a mouse model of rheumatoid arthritis (RA). This compound targets osteoclast activity and the NF-κB pathway, suggesting potential for RA treatment.
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) is a systemic autoimmune disease causing joint damage and reduced quality of life.
- RA pathogenesis is complex, with some patients resistant to current therapies.
- Salubrinal shows promise for bone health, but its role in RA requires investigation.
Purpose of the Study:
- To investigate the therapeutic effects of Salubrinal on collagen-induced arthritis (CIA) in mice.
- To elucidate the underlying mechanisms of Salubrinal's action in arthritis.
Main Methods:
- Collagen-induced arthritis (CIA) was induced in DBA/1J mice.
- Mice were treated with Salubrinal.
- Clinical scores, joint damage, bone destruction, osteoclast formation, and gene expression were assessed.
- The RANKL-induced NF-κB signaling pathway and P65 degradation were analyzed.
Main Results:
- Salubrinal treatment significantly decreased clinical scores and inhibited joint/bone destruction in CIA mice.
- Salubrinal reduced osteoclast numbers and suppressed osteoclast formation and function.
- The compound downregulated osteoclast-related gene expression and inhibited the RANKL-induced NF-κB pathway.
- Salubrinal promoted P65 degradation via the ubiquitin-proteasome system, restraining osteoclastogenesis.
Conclusions:
- Salubrinal ameliorates arthritis in a CIA mouse model by inhibiting osteoclastogenesis through the NF-κB pathway.
- Salubrinal demonstrates potential as a therapeutic agent for rheumatoid arthritis.
- This study expands the therapeutic applications of Salubrinal for bone destruction-related diseases.
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