ABSTRACT
Sex difference has shown in the arthritis diseases in human population and animal models. We investigate how the sex and symmetry vary among mouse models with different genomic backgrounds. Disease data of sex and limbs accumulated in the past more than two decades from four unique populations of murine arthritis models were analyzed. They are (1) interleukin-1 receptor antagonist (IL-1ra) deficient mice under Balb/c background (Balb/c KO); (2) Mice with collagen II induced arthritis under DBA/1 background; (3) Mice with collagen II induced arthritis under C57BL/6 (B6) background and (4) A F2 generation population created by Balb/c KO X DBA/1 KO.Our data shows that there is a great variation in sexual dimorphism for arthritis incidence and severity of arthritis in mice harboring specific genetic modifications. For a F2 population, the incidence of arthritis was 57.1% in female mice and 75.6% in male mice. There was a difference in severity related to sex in two populations: B6.DR1/ B6.DR4 (P < 0.001) and F2 (P = 0.023) There was no difference Balb/c parental strain or in collagen-induced arthritis (CIA) in DBA/1 mice. Among these populations, the right hindlimbs are significantly higher than the scores for the left hindlimbs in males (P < 0.05). However, when examining disease expression using the collagen induced arthritis model with DBA/1 mice, sex-dimorphism did not reach statistical significance, while left hindlimbs showed a tendency toward greater disease expression over the right. Sexual dimorphism in disease expression in mouse models is strain and genomic background dependent. It sets an alarm that potential variation in sexual dimorphism among different racial and ethnic groups in human populations may exist. It is important to not only include both sexes and but also pay attention to possible variations caused by disease expression and response to treatment in all the studies of arthritis in animal models and human populations.
ABSTRACT
Collagen induced arthritis (CIA)is an animal model that in many ways resembles rheumatoid arthritis (RA). CIA can be induced in susceptible animals by immunization with type II collagen (CII). Like RA,CIA is characterized by intense joint inflammation and destruction.On histological examination,there is synovitis accompanied by erosion of cartilage and subchondral bone. Autoanti-bodies to CII initiate joint inflammation by binding to articular cartilage,forming antigen-antibody complexes locally and activating hemolytic complement. Susceptibility to CIA in mice is linked to the expression of specific class II MHC Molecules,which dictate the T cell determinants on CII,and therefore,the subsets of T cells that can be activated by CII.In addition to activation of B cells reactive to CII,the T cells stimulate monocytes/macrophages.These cells amplify the inflammatory cascade by secretion of proinflammatory monokines, including TNF-alpha and IL-1,leading to the production of other proinflammatory proteins,including matrix metalloproteinases (MMPs).The importance of CIA lies in its possible relationship to arthritis in humans.Progress in understanding CIA has contributed to the development of new therapies for RA.In addition,it has been found that mice with human HLA-DR1,DR4 and HLA-DQ8 transgenes,which have been demonstrated to be the susceptibility markers for RA, confer susceptibility to CIA.These observations coupled with the finding of T cells and B cells reactive with CII in the inflamed joints of RA patients establish the potential role of CII autoimmunity in the pathogenesis of RA.