Abstract
Abstract We have recently proposed that the shared epitope (SE) may contribute to rheumatoid arthritis (RA) pathogenesis by acting as a ligand that activates pro-arthritogenic signal transduction events. In order to examine this hypothesis, here we determined the arthritogenic effect of a novel small SE-mimetic compound, c(HS4-4). In this study, we show that c(HS4-4), containing the SE primary sequence motif QKRAA, interacted with the SE receptor calreticulin, potently activated reactive oxygen species (ROS) and nitric oxide (NO) production and markedly facilitated OC differentiation and function in vitro. The pro-osteoclastogenic potency of c(HS4-4) was 100,000 to 1,000,000-fold higher than the potency of a recently described linear SE peptidic ligand. When administered at low-nanogram doses to collagen-induced arthritis (CIA) mice, c(HS4-4) significantly facilitated arthritis onset, increased disease incidence and severity, augmented bone destruction, and increased OC abundance in synovial tissues and osteoclastogenic propensities of bone marrow-derived cells. In conclusion, c(HS4-4), a small SE-mimetic compound with drug-like properties, potently activates OC-mediated bone damage and disease severity in inflammatory arthritis. These findings support the hypothesis that the SE acts as signal transduction ligand that activates an arthritogenic pathway, and attest to the druggability of this pathway.
Published Version
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