Cartilage oligomeric matrix protein induction of chronic arthritis in mice.
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 x DBA/1)F1, (BALB/c x B10.Q)F1, Ncf1 mutated, H-2Aq, H-2Ap, 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-2q and H-2p MHC haplotypes allowed the initiation of COMPIA. Using H-2Aq-transgenic and H-2Ap-transgenic mice, we demonstrated a role of both the Aq and Ep 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.


CONCLUSIONS
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.
Carlsen
Stefan
S
Lund University, Lund, Sweden.
Nandakumar
Kutty Selva
KS
Bäcklund
Johan
J
Holmberg
Jens
J
Hultqvist
Malin
M
Vestberg
Mikael
M
Holmdahl
Rikard
R
D000818:Animals; D000906:Antibodies / Q000097:blood; D001168:Arthritis / Q000097:blood / Q000139:chemically induced / Q000276:immunology*; D064236:Cartilage Oligomeric Matrix Protein; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000009:adverse effects / Q000097:blood / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000009:adverse effects / Q000097:blood / Q000276:immunology*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D064235:Matrilin Proteins; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D051381:Rats
D000906:Antibodies; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1