Research Article Synovial Knee Joint in Rheumatoid Arthritis Treated with TDZD-8: An Association between Synovial Fibrosis and the TNF-/VEGF/-SMA Axis

Background and Objective: Inflammation and fibrosis-induced swelling are key features in rheumatoid arthritis (RA) that causes joint damage and disability. The inflammatory biomarker, Tumor Necrosis Factor-Alpha (TNF-alpha) is known to be involved in RA pathology. The RA can cause synovial membrane fibrosis through the activation of the TNF-alpha/Vascular Endothelial Growth Factor (VEGF)/alpha-smooth muscle actin (alpha-SMA) pathway, which can be inhibited by TDZD-8, the inhibitor of the enzyme Glycogen Synthase Kinase-3 beta (GSK3 beta). Materials and Methods: The RA was induced in rats using active immunization by injection with collagen type II (COII). A matched group of rats was treated with 1 mg kg(-1) TDZD-8 (COII+TDZD-8) for 3 weeks after the immunization protocol. At the end of the experiment (week 6), blood and synovium tissue samples were collected. Results: The development of RA was established and confirmed by a sharp increase in the blood levels of the rheumatoid factor (RF) as well as swelling and deformities in the hind limbs. Blood levels of TNF-alpha and synovium tissue levels of VEGF, alpha-SMA and collagen fibers were significantly (p<0.0001) increased in the model group (RA). The TDZD-8 was significantly associated with the inhibition of all these parameters and curing the swelling and deformities in the hind limbs. In addition, a significant correlation between RF, TNF-alpha, VEGF, alpha-SMA and synovial fibrosis was observed. Conclusion: These findings in a rat model of rheumatoid arthritis that affects synovial knee joint demonstrate an association between the fibrosis in the synovial membrane and the synovium TNF-alpha/VEGF/alpha-SMA axis while being treated by TDZD-8.