Biology Reference
In-Depth Information
isolation in rats and rabbits, and the aging process
[86]
. The underlying rationale for
the experimental approach used was that most published studies dealing with hor-
mone or immune changes in the above-mentioned situations were performed at sin-
gle time points in the 24-hour span—an important drawback in view of the circadian
nature of hormone release and immune function; also, most of the preceding manipu-
lations employed disrupt circadian rhythmicity. The results obtained in the rat model
of adjuvant arthritis are reviewed in section 6.4.
6.4 Rat Adjuvant Arthritis as an Experimental
Model of Rheumatoid Arthritis
Rheumatoid arthritis is a systemic inflammatory disorder that mainly affects the diar-
throdial joint. It is the most common form of inflammatory arthritis and affects about
1% of the population, in a female/male ratio of 2.5/1. The disease can occur at any
age, but it is most common among those aged 40-70 years. The geographic distri-
bution of rheumatoid arthritis is worldwide, with a notably low prevalence in rural
areas
[87-89]
.
Although it initially presents as a symmetrical polyarticular synovitis with promi-
nent hand involvement, rheumatoid arthritis has multiple potential systemic manifes-
tations. The clinical course of the disorder is extremely variable, ranging from mild,
self-limiting arthritis to rapidly progressive multisystem inflammation with profound
morbidity and mortality. Fever and weight loss can be part of the acute symptoms,
while splenomegaly, vasculitis, neutropenia, and amyloidosis are some of the com-
plications that may occur in patients with long-standing disease
[87,90,91]
.
Rheumatoid arthritis is a T-cell-driven autoimmune process associated with the
production of autoantibodies. Rheumatoid arthritis is initiated by CD4 T cells,
which amplify the immune response by stimulating other mononuclear cells, syn-
ovial fibroblasts, chondrocytes, and osteoclasts. The release of cytokines, especially
TNF-, IL-1, and IL-6, causes synovial inflammation. In rheumatoid arthritis, the
inflammatory process, usually tightly regulated by mediators that initiate and maintain
inflammation and mediators that shut the process down, becomes imbalanced, leaving
inflammation unchecked and resulting in the destruction of cartilage and bone.
Efforts to develop safer and more effective treatments for rheumatoid arthritis rely
heavily on the availability of suitable animal models
[92,93]
. Among these models, rat
adjuvant arthritis is widely employed
[94]
. Hallmarks of this rat model are reliable onset
and progression of easily measurable, polyarticular inflammation, marked bone resorp-
tion, and periosteal bone proliferation. Induction of adjuvant disease can be done either
with Freund's complete adjuvant supplemented with mycobacterium, or by injecting
synthetic adjuvants
[92-94]
. The pathogenesis for development of adjuvant disease fol-
lowing injection of mycobacterial preparations is not fully understood, although a cross-
reactivity of mycobacterial-wall antigens with cartilage proteoglycans occurs.
After FCA injection into rats, the inflammatory disease of the joints shows four stages
in its time course: preclinical (first week), acute (weeks 2-4), postacute (weeks 5-8),
