Blocking translationally controlled tumor protein attenuate
aggressiveness of fibroblast-like synoviocytes and ameliorates
collagen-induced arthritis
Abstract
Background and Purpose Histamine releasing factor/translationally
controlled tumor protein (HRF/TCTP) stimulates cancer progression and
allergic responses, but the role of HRF/TCTP remains undefined in
rheumatoid arthritis (RA). In this study, we explored the pathogenic
significance of HRF/TCTP and evaluated the therapeutic effects of
HRF/TCTP blockade in RA. Experimental Approach HRF/TCTP transgenic (TG)
and knockdown (KD) mice with collagen-induced arthritis (CIA) were used
to determine experimental phenotypes of RA. HRF/TCTP levels were
measured in the sera of RA patients and compared to those with
osteoarthritis (OA), ankylosing spondylitis, Behçet’s disease, and
healthy controls. HRF/TCTP expression was also assessed in the synovium
and fibroblast-like synoviocytes (FLS) 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-FLS and
CIA mice. Key Results Our clinical, radiological, histological, and
biochemical analyses indicate that inflammatory responses and joint
destruction were higher in HRF/TCTP TG mice, and lower in KD mice,
compared to that in wild-type littermates. HRF/TCTP levels were higher
in the sera, synovial fluid, synovium, and FLS of patients with RA than
control groups. Serum levels of HRF/TCTP correlated well with disease
activity of RA. Tumor-like aggressiveness of RA-FLS 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. Conclusion and Implications Our
results indicate that HRF/TCTP is a novel biomarker and therapeutic
target for the diagnosis and treatment of RA.