THE ROLE OF GUANYLATE BINDING PROTEIN 5 IN THE PATHOGENESIS OF RHEUMATIC DISEASES

Mahamudul Haque

Rheumatoid Arthritis (RA) is an auto-immune disease characterized by chronic inflammation of joints, bone and tissue destruction, systemic complications, and early death. In RA joints, immune cells, including B cells, T cells, macrophages, and neutrophils infiltrate into the synovium and produce proinflammatory cytokines. The resident cell in the synovium, the synovial fibroblast (SF), also produces chemokines such as IL-6, IL-8, CXCL-5, and matrix-degrading proteins to perpetuate inflammation and tissue destruction. Studies have shown that interferon-gamma (IFN-γ), an immunomodulatory cytokine, has a protective effect in RA pathogenesis. However, the IFN-γ inducible proteins responsible for the protective action have never been studied in RA. Our preliminary study suggests that Guanylate Binding Protein 5 (GBP5), one IFN-γ inducible protein, is upregulated in rheumatoid arthritis synovial tissues (RASTs). We hypothesize that increased expression of GBP5 might contribute to enhance or resolve the inflammation in RA. To address our hypothesis, we characterized the expression of GBP5 in non-diseased synovial tissues (NLSTs) and RASTs. We then analyzed the molecular mechanism by which GBP5 exerts its action in RASFs. Following inhibition of GBP5 by transient knockdown and over-expression using a lentiviral delivery system, we evaluated the levels of IL-6, IL-8, CXCL-5, and MMPs in RASFs. Finally, we tested the efficacy of GBP5 as a therapeutic target using an animal model of RA. The rat adjuvant-induced arthritis model showed that loss of GBP5 in the joint caused increased inflammation and tissue destruction in the rat joints. We also observed enhanced bone loss and necrosis in the GBP5 knockdown group compared to the control group. We also found GBP5 modulates the effect of TNF alpha inducible gene 6 (TSG6) in osteoarthritis synovial fibroblasts (OASF). TSG6 is characterized as an anti-inflammatory protein in different inflammatory arthritis models, and GBP5 was found to modulate the tissue-protective effect through TSG6. This study has helped us to understand the role of GBP5 in both osteoarthritis and rheumatoid arthritis pathogenesis and will help to determine the potential role of this novel protein as a new treatment option in inflammatory arthritis.

THE ROLE OF GUANYLATE BINDING PROTEIN 5 IN THE PATHOGENESIS OF RHEUMATIC DISEASES

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