title: Shared epitope-antagonistic ligands: a new therapeutic strategy in mice with erosive arthritis.
abstract: OBJECTIVE
  The mechanisms underlying bone damage in rheumatoid arthritis (RA) are incompletely understood. We recently identified the shared epitope (SE), an HLA-DRB1-coded 5-amino acid sequence motif carried by the majority of RA patients as a signal transduction ligand that interacts with cell surface calreticulin and accelerates osteoclast (OC)-mediated bone damage in collagen-induced arthritis (CIA). Given the role of the SE/calreticulin pathway in arthritis-associated bone damage, we sought to determine the therapeutic targetability of calreticulin.
  
  
  METHODS
  A library of backbone-cyclized peptidomimetic compounds, all carrying an identical core DKCLA sequence, was synthesized. The ability of these compounds to inhibit SE-activated signaling and OC differentiation was tested in vitro. The effect on disease severity and OC-mediated bone damage was studied by weekly intraperitoneal administration of the compounds to DBA/1 mice with CIA.
  
  
  RESULTS
  Two members of the peptidomimetics library were found to have SE-antagonistic effects and antiosteoclast differentiation effects at picomolar concentrations in vitro. The lead mimetic compound, designated HS(4-4)c Trp, potently ameliorated arthritis and bone damage in vivo when administered in picogram doses to mice with CIA. Another mimetic analog, designated HS(3-4)c Trp, was found to lack activity, both in vitro and in vivo. The differential activity of the 2 analogs depended on minor differences in their respective ring sizes and correlated with distinctive geometry when computationally docked to the SE binding site on calreticulin.
  
  
  CONCLUSIONS
  These findings identify calreticulin as a novel therapeutic target in erosive arthritis and provide sound rationale and early structure/activity relationships for future drug design.
authors.affiliation: University of Michigan School of Medicine, Ann Arbor.
authors.forename: Song
authors.initials: S
authors.lastname: Ling
authors.affiliation: University of Michigan School of Medicine, Ann Arbor.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: University of Michigan School of Medicine, Ann Arbor.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Fu
authors.affiliation: University of Michigan School of Medicine, Ann Arbor.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colletta
authors.affiliation: The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.affiliation: University of Michigan School of Medicine, Ann Arbor.
authors.forename: Joseph
authors.initials: J
authors.lastname: Holoshitz
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D037282:Calreticulin / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D000939:Epitopes; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D037282:Calreticulin; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D019151:Peptide Library; D010455:Peptides