Abstract
Objective
To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP‐induced arthritis (COMPIA).
Methods
Native (pentameric) and denatured (monomeric) COMP purified from a rat chondrosarcoma was injected into mice with Freund's adjuvant to induce arthritis. C3H.NB, C3H.Q, B10.P, B10.Q, (B10.Q × DBA/1)F~1~, (BALB/c × B10.Q)F~1~, Ncf1 mutated, H‐2A^q^, H‐2A^p^, and human DR4+‐transgenic mice were used. Anti‐COMP antibodies and COMP levels in the immune sera were analyzed, and passive transfer of arthritis with purified immune sera was tested.
Results
Immunization with rat COMP induced a severe, chronic, relapsing arthritis, with a female preponderance, in the mice. The disease developed in C3H.NB mice, but not in B10.P mice, although they share the same MHC haplotype. Both H‐2^q^ and H‐2^p^ MHC haplotypes allowed the initiation of COMPIA. Using H‐2A^q^–transgenic and H‐2A^p^–transgenic mice, we demonstrated a role of both the A^q^ and E^p^ class II molecules in this model. Interestingly, the introduction of a mutation in the Ncf1 gene, which is responsible for the reduced oxidative burst phenotype, into the COMPIA‐resistant B10.Q mouse strain rendered them highly susceptible to arthritis. In addition, the transfer of anti‐COMP serum was found to induce arthritis in naive mice. Mice transgenic for the rheumatoid arthritis (RA)–associated DR4 molecule were found to be highly susceptible to COMPIA.
Conclusion
Using rat COMP, we have developed a new and unique mouse model of chronic arthritis that resembles RA. This model will be useful as an appropriate and alternative model for studying the pathogenesis of RA.