title: A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis.
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.
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109-5680, USA.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Fu
authors.forename: Song
authors.initials: S
authors.lastname: Ling
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianyi
authors.initials: J
authors.lastname: Yang
authors.forename: Shirly
authors.initials: S
authors.lastname: Naveh
authors.forename: Margaret
authors.initials: M
authors.lastname: Hannah
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Holoshitz
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D032701:Biomimetics; D002454:Cell Differentiation; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology*; D020349:Surface Plasmon Resonance
chemical_list: D000939:Epitopes; D059811:HLA-DRB1 Chains