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.
Highlights
Rheumatoid arthritis (RA), a chronic inflammatory and systemic autoimmune disease that affects 1% of the general population[1], is characterized by destructive joint inflammation and systemic comorbidities, including pathogenesis has improved, and therapeutic strategies against RA have been revolutionized by the development of targeted drugs such as tumor necrosis factor inhibitors, interleukin-6 (IL-6) blockers, B-cell depletion agents, and inhibitors of T-cell costimulation and Janus kinases[5].an appreciable percentage of patients experience refractory disease and interrupt treatment due to the risk of infection and malignancy[6,7]
We examined whether Histamine releasing factor (HRF)/TCTP knockdown (KD) would exert an antiarthritic effect upon collagen-induced arthritis (CIA) generation
These results show that HRF/TCTP enhanced the manifestation of CIA, but knockdown of HRF/TCTP inhibited the arthritic inflammation and joint destruction observed in CIA
Summary
Rheumatoid arthritis (RA), a chronic inflammatory and systemic autoimmune disease that affects 1% of the general population[1], is characterized by destructive joint inflammation and systemic comorbidities, including pathogenesis has improved, and therapeutic strategies against RA have been revolutionized by the development of targeted drugs such as tumor necrosis factor inhibitors, interleukin-6 (IL-6) blockers, B-cell depletion agents, and inhibitors of T-cell costimulation and Janus kinases[5].an appreciable percentage of patients experience refractory disease and interrupt treatment due to the risk of infection and malignancy[6,7]. Rheumatoid arthritis (RA), a chronic inflammatory and systemic autoimmune disease that affects 1% of the general population[1], is characterized by destructive joint inflammation and systemic comorbidities, including pathogenesis has improved, and therapeutic strategies against RA have been revolutionized by the development of targeted drugs such as tumor necrosis factor inhibitors, interleukin-6 (IL-6) blockers, B-cell depletion agents, and inhibitors of T-cell costimulation and Janus kinases[5]. The investigation of new cytokines or cellular mechanisms that could be potential targets for RA treatment or prevention remains of high importance. Pannus provides a microenvironment that sustains autoimmunity and supports cellular and cytokine activities crucial for joint destruction[10,11]. Recurrent or refractory RA likely depends on the persistent immunopathologic activity of resident RA-FLSs within pannus[15]. Disrupting FLSspecific immunopathology may prevent joint destruction by mechanisms that do not contribute to systemic immunosuppression and increased infection risk[16,17,18]. Interfering with RA-FLS proliferation and invasion may contribute to effective and long-term disease control
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