Abstract
We have recently proposed that the shared epitope (SE) may contribute to rheumatoid arthritis pathogenesis by acting as a ligand that activates proarthritogenic signal transduction events. To examine this hypothesis, in this study we characterized a novel small SE-mimetic compound, c(HS4-4), containing the SE primary sequence motif QKRAA, which was synthesized using a backbone cyclization method. The SE-mimetic c(HS4-4) compound interacted strongly with the SE receptor calreticulin, potently activated NO and reactive oxygen species production, and markedly facilitated osteoclast 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 in vivo at nanogram doses, c(HS4-4) enhanced Th17 expansion, and in mice with collagen-induced arthritis it facilitated disease onset, increased disease incidence and severity, enhanced osteoclast abundance in synovial tissues and osteoclastogenic propensities of bone marrow–derived cells, and augmented bone destruction. In conclusion, c(HS4-4), a highly potent small SE-mimetic compound enhances bone damage and disease severity in inflammatory arthritis. These findings support the hypothesis that the SE acts as a signal transduction ligand that activates a CRT-mediated proarthritogenic pathway.
Footnotes
This work was supported by National Institutes of Health Grants GM088560, AR059085, and AR048310 (to J.H.), and GM083107 and GM084222 (to Y.Z.).
Abbreviations used in this article:
- BM
- bone marrow
- BW
- body weight
- CIA
- collagen-induced arthritis
- CII
- collagen type II
- CRT
- calreticulin
- DLN
- draining lymph node
- micro-CT
- micro–computerized tomography
- OC
- osteoclast
- RA
- rheumatoid arthritis
- RANKL
- receptor activator for NF-κB ligand
- ROS
- reactive oxygen species
- SE
- shared epitope
- SPR
- surface plasmon resonance
- TRAP
- tartrate-resistant acid phosphatase.
- Received November 26, 2012.
- Accepted June 21, 2013.
- Copyright © 2013 by The American Association of Immunologists, Inc.