NDLI: Shared epitope-antagonistic ligands: a new therapeutic strategy in mice with erosive arthritis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ling, Song Liu, Ying Fu, Jiaqi Colletta, Alessandro Gilon, Chaim Holoshitz, Joseph
Description	Author Affiliation: Ling S ( University of Michigan School of Medicine, Ann Arbor.); Liu Y ( University of Michigan School of Medicine, Ann Arbor.); Fu J ( University of Michigan School of Medicine, Ann Arbor.); Colletta A ( University of Michigan School of Medicine, Ann Arbor.); Gilon C ( The Hebrew University of Jerusalem, Jerusalem, Israel.); Holoshitz J ( University of Michigan School of Medicine, Ann Arbor.)
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. CONCLUSION: 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.
File Format	HTM / HTML
ISSN	23265191
e-ISSN	23265205
DOI	10.1002/art.39158
Journal	Arthritis & Rheumatology
Issue Number	8
Volume Number	67
Language	English
Publisher	Wiley
Publisher Date	2015-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Rheumatology Arthritis, Experimental Metabolism Arthritis, Rheumatoid Bone And Bones Drug Effects Calreticulin Histocompatibility Antigens Class Ii Osteoclasts Peptides Pharmacology Animals Immunology Cell Differentiation Disease Models, Animal Epitopes In Vitro Techniques Ligands Mice Molecular Docking Simulation Peptide Library Signal Transduction Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology Rheumatology

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Shared Epitope Antagonistic Ligands - A New Therapeutic Strategy in Mice with Erosive Arthritis

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