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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 proosteoclastogenic 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 collageninduced 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.

Original languageEnglish
Pages (from-to)2096-2103
Number of pages8
JournalJournal of Immunology
Volume191
Issue number5
DOIs
StatePublished - 1 Sep 2013

Fingerprint

Dive into the research topics of 'A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis'. Together they form a unique fingerprint.

Cite this