Inhibition of GSK3β protects against collagen type II-induced arthritis associated with a decrease in synovial
Norah M Alzamil1, Faten A Alradini1, Bahjat Al-Ani2
1Department of Clinical Science, Family Medicine, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
Abstract:
We sought to determine whether TDZD-8, the inhibitor of the glycogen synthase kinase-3β (GSK3β), can protect the synovial membrane of the knee joint against injuries induced by collagen type II immunization (CIA) possibly via the downregulation of synovial leukocyte infiltration, endoplasmic reticulum stress (ERS), and autophagy. The model group of rats (CIA) were immunized over a period of 3 weeks with collagen type II, whereas the treated group of rats (CIA + TDZD-8) were treated with TDZD-8 (1 mg/kg) for 21 days after the completion of the immunization regimen. All rats were then killed at week 6. Harvested synovial tissues were prepared for immunohistochemistry staining, and synovial homogenates were assayed for biomarkers of ERS, autophagy, apoptosis, and cell survival and proliferation. In addition, blood samples were assayed for biomarkers of arthritis. Synovial tissue images showed that CIA enhanced leukocyte recruitment as demonstrated by an increased CD45+ (leukocyte common antigen) immunostaining, which was markedly decreased by TDZD-8. TDZD-8 also significantly (P < .05) inhibited collagen-induced autophagy biomarkers Beclin-1 and LC3II, the ERS biomarkers GRP-78, IRE1-α, XBPIs, and eIF2a, and the survival protein Bcl-2. Whereas, the collagen-induced proliferative biomarkers Akt and mTOR were not inhibited by TDZD-8, and CIA inhibited the apoptotic proteins CHOP and cleaved caspase-3, which were augmented by TDZD-8. We further demonstrated a significant (P < .05) correlation between autoantibodies generated during the course of arthritis and biomarkers of ERS and autophagy. We conclude that TDZD-8 inhibits CIA and decreases synovial leukocyte infiltration, ERS, and autophagy, which is independent of Akt/mTOR signalling.
Insights
TDZD-8, a GSK3β inhibitor, reduces knee joint inflammation in rats with collagen-induced arthritis. It lowers leukocyte infiltration, endoplasmic reticulum stress, and autophagy, offering a potential therapeutic strategy for arthritis.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Rheumatoid arthritis involves synovial membrane injury.
- Collagen-induced arthritis (CIA) is a common animal model for rheumatoid arthritis.
- Glycogen synthase kinase-3β (GSK3β) plays a role in inflammatory pathways.
Purpose of the Study:
- To investigate the protective effects of TDZD-8, a GSK3β inhibitor, on the synovial membrane in a rat model of CIA.
- To determine if TDZD-8 downregulates synovial leukocyte infiltration, endoplasmic reticulum stress (ERS), and autophagy.
- To explore the impact of TDZD-8 on apoptotic and proliferative biomarkers in CIA.
Main Methods:
- Rats were immunized with collagen type II to induce arthritis.
- TDZD-8 was administered to the treatment group after immunization.
- Synovial tissues and blood were analyzed for leukocyte infiltration, ERS, autophagy, apoptosis, and proliferation markers.
- Immunohistochemistry and biochemical assays were performed.
Main Results:
- TDZD-8 significantly decreased CD45+ leukocyte infiltration in synovial tissues.
- TDZD-8 inhibited collagen-induced autophagy (Beclin-1, LC3II) and ERS (GRP-78, IRE1-α, XBPIs, eIF2a) biomarkers.
- TDZD-8 augmented pro-apoptotic proteins (CHOP, cleaved caspase-3) and did not affect proliferative markers (Akt, mTOR).
- A correlation was found between arthritis autoantibodies and ERS/autophagy biomarkers.
Conclusions:
- TDZD-8 demonstrates protective effects against CIA in rats.
- The mechanism involves the downregulation of synovial leukocyte infiltration, ERS, and autophagy.
- These effects are independent of Akt/mTOR signaling pathways.
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