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A Small Shared Epitope–Mimetic Compound Potently Accelerates Osteoclast-Mediated Bone Damage in Autoimmune Arthritis

Jiaqi Fu, Song Ling, Ying Liu, Jianyi Yang, Shirly Naveh, Margaret Hannah, Chaim Gilon, Yang Zhang and Joseph Holoshitz
J Immunol September 1, 2013, 191 (5) 2096-2103; DOI: https://doi.org/10.4049/jimmunol.1203231
Jiaqi Fu
*Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109;
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Song Ling
*Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109;
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Ying Liu
*Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109;
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Jianyi Yang
†Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI 48109; and
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Shirly Naveh
‡Institute of Chemistry, Hebrew University of Jerusalem, 91904 Jerusalem, Israel
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Margaret Hannah
*Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109;
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Chaim Gilon
‡Institute of Chemistry, Hebrew University of Jerusalem, 91904 Jerusalem, Israel
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Yang Zhang
†Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI 48109; and
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Joseph Holoshitz
*Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109;
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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.
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The Journal of Immunology: 191 (5)
The Journal of Immunology
Vol. 191, Issue 5
1 Sep 2013
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A Small Shared Epitope–Mimetic Compound Potently Accelerates Osteoclast-Mediated Bone Damage in Autoimmune Arthritis
Jiaqi Fu, Song Ling, Ying Liu, Jianyi Yang, Shirly Naveh, Margaret Hannah, Chaim Gilon, Yang Zhang, Joseph Holoshitz
The Journal of Immunology September 1, 2013, 191 (5) 2096-2103; DOI: 10.4049/jimmunol.1203231

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A Small Shared Epitope–Mimetic Compound Potently Accelerates Osteoclast-Mediated Bone Damage in Autoimmune Arthritis
Jiaqi Fu, Song Ling, Ying Liu, Jianyi Yang, Shirly Naveh, Margaret Hannah, Chaim Gilon, Yang Zhang, Joseph Holoshitz
The Journal of Immunology September 1, 2013, 191 (5) 2096-2103; DOI: 10.4049/jimmunol.1203231
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