Saeed M. Alqahtani1; Zenat Khired; Mohammad Y. Alshahrani; Norah M. Alzamil; Samaa S. Kamar; Mohamed Abd Ellatif; Mohammad Dallak; Bahjat Al-Ani & Amal F. Dawood

Rheumatoid arthritis (RA) that affects the synovial knee joint causes swelling of the synovial membrane and tissue damage. Interleukin-17A (IL-17A) and the enzyme glycogen synthase kinase-3β (GSK3β) are involved in the pathogenesis of RA. The link between IL-17A, GSK3β, the oxidative stress, and the profibrogenic marker alpha-smooth muscle actin (α-SMA) with and without TDZD-8, GSK3β inhibitor has not been studied before. Consequently, active immunization of rats was performed to induce RA after three weeks using collagen type II (COII) injections. The treated group received daily injection of 1 mg/kg TDZD-8 for 21 days following the immunization protocol (COII+TDZD-8). Blood and synovium tissue samples were harvested at the end of the experiment. RA development was confirmed as corroborated by a substantial increase in blood levels of the highly specific autoantibody for RA, anti- citrullinated protein antibody as well as augmentation of reactive oxidative species (ROS) levels measured as lipid peroxidation. RA induction also increased synovium tissue levels of IL-17A and the profibrogenic marker, α-SMA. All these parameters seemed to be significantly (p<0.0001) ameliorated by TDZD-8. Additionally, a significant correlation between IL-17A, ROS, and α-SMA and biomarkers of RA was observed. Thus, knee joint synovium RA induction augmented IL-17A/GSK3β/ROS/α-SMA axis mediated arthritis in a rat model of RA, which was inhibited by TDZD-8.

KEY WORDS: Rheumatoid arthritis; IL-17A; GSK3β; ROS; α-SMA; Fibrosis; TDZD-8.

ALQAHTANI, S. M.; KHIRED, Z.; ALSHAHRANI, M. Y.; ALZAMIL, N. M.; KAMAR, S. S.; ELLATIF, M. A.; DALLAK, M.; AL-ANI, B. & DAWOOD, A. F. A rat model of rheumatoid arthritis: TDZD-8 is associated with the protection against the induction of the synovium knee joint IL-17A/GSK3β/ROS/α-SMA axis of fibrosis. Int. J. Morphol., 41(2):583-590, 2023.