Blockade of translationally controlled tumor protein attenuated the aggressiveness of fibroblast-like synoviocytes and ameliorated collagen-induced arthritis

Abstract

Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP in rheumatoid arthritis (RA) remains undefined. In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine the experimental phenotypes of RA. HRF/TCTP levels in the sera of RA patients were measured and compared to those from patients with osteoarthritis (OA), ankylosing spondylitis, Behçet’s disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLSs) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLSs and CIA mice. Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels in the sera, synovial fluid, synovium, and FLSs were higher in patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with RA disease activity. The tumor-like aggressiveness of RA-FLSs was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice and had no detrimental effects in a murine tuberculosis model. Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA.

Rheumatoid arthritis: A problem protein to target for treatment

A protein known to stimulate cancer and allergies has been implicated as an exacerbating factor in rheumatoid arthritis (RA); inhibiting its activity or blocking its production could offer options to prevent or treat RA. Previous research had identified high levels of histamine-releasing factor (HRF), also known as translationally controlled tumor protein (TCTP), in patients with RA. Its role in the destruction of joint tissue seen in RA was investigated by researchers in South Korea led by Sang-Il Lee at Gyeongsang National University, Jinju, and Kyunglim Lee at Ewha Womans University, Seoul. They examined HRF/TCTP’s activity and effects in fibroblast-like synoviocytes from RA patients and in a mouse model of RA and confirmed it can cause joint inflammation and damage. A molecule that inhibits HRF/TCTP activity reduced the severity of RA-like effects, suggesting potential new therapies.