Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects about 1% of the population globally; females being three times more prone to its attack than males. Recent research has contributed much about the causative factors that exaggerate the pathogenesis of arthritis but there is still a lack of knowledge in the etiology of the disease. It is for this reason, alongwith the need for more effective and less toxic remedies, the arthritis animal models are being studied. It is believed that these animal models, regardless of the method of induction, will predict the aetiopathogenetic mechanisms involved in the human disease. Some of these animal models resemble the human disease with respect to clinical features and histopathology; but, unfortunately this resemblance does not apply to the entire spectrum of manifestations found in rheumatoid arthritis. Animal models are usually used by pharmaceutical companies and other research labs for the testing of new therapeutic agents, analysis of genetic susceptibility factors and search for biomarkers of RA and other inflammatory diseases, thus leading to significant advancements in the search of key therapeutic molecules as well as targets for this destructive disease. So, here I am reviewing the information available on the experimental animal models of arthritis, which share a significant number of clinical and pathological features similar to human RA and are most commonly used for pharmaceutical testing in RA.
1. Collagen-induced arthritis (CIA)
This is the well established in vivo model that has been used for studies of new drugs for therapeutic intervention in RA. CIA can be induced in both male and female rats (Sprague-dawley, Wistar, lewis etc.) of 5-6 weeks age-group, mice (DBA-1J, B10) and primates (monkeys) following immunization with type II collagen (CII) in adjuvant. CII is the principal protein found in the articular and hyaline cartilage, constitutes about 50% of all cartilage proteins and 80-90% of collagen of articular cartilage. Intradermal injection of homologous or heterologous (porcine, chick, bovine) type II collagen in freund's complete adjuvant (FCA) induces a chronic polyarthritis in rats. Primary immunization is followed by a booster dose. The onset of CIA usually starts around 12-16 days after primary immunization and the incidence of CIA is never 100%. The disease progression is asymmetrical and any combination of joints can be affected upto varying degrees. The onset of disease is characterized by marked cartilage destruction, bone resorption, moderate to marked synovial cell proliferation, polymorphonuclear cells infiltration and periarticular inflammation.
Both CIA and RA share the immunological and pathological features that are dependent on both humoral and cellular immunity to the immunizing antigen. Use of CIA as a model for RA is based principally on pathological similarities between the two diseases like both CIA and RA show similar patterns of synovial hyperplasia, inflammatory cell infiltration, pannus formation and erosion of cartilage and bone. Susceptibility to both diseases is strongly associated with MHC class II genes, suggesting similar immunological processes. In contrast, there are striking differences between the two, as CIA is a time-dependent model and can be induced particularly in some genetically susceptible strains of animals only.
2. Adjuvant-induced arthritis (AIA)
It is also an experimental model of polyarthritis that has been widely used for the preclinical testing of anti-arthritic agents for their use as therapeutics in the later stage. AIA can be induced by a single intradermal injection of FCA containing heat attenuated mycobacterium tuberculosis extract, in the subplantar region of the hind foot and at the base of the tail. The symptoms usually start to appear 8-12 hours after immunization and about 9 days later in the contralateral paw and other organs. The disease progresses till 15-20 days after the immunization and arthritic lesions (secondary symptoms) begin to appear at the site of injection from 7-9th day onwards. The characteristic symptoms of this model include the reliable onset and progression of disease with polyarticular inflammation, periosteal bone proliferation and resorption. Cartilage destruction that occurs is proportionately mild in comparison to that occurs in human RA.
3. Carrageenan induced paw edema
Paw edema or inflammation in rats or mice is frequently used for evaluation of anti-inflammatory activity. It can be induced by an injecting carrageenan into the left hind paw of each animal in the sub plantar aponeurosis. This model functions maximally 3-5 hours after carrageenan injection and the whole process of disease progression is marked by two distinct phases:
Phase I: It lasts about two and a half hours and associated with the rise of inflammatory mediators serotonin, histamine and kinins.
Phase II: It starts after the end of phase I and ends at about 6 hours after carrageenan injection. It is characterized by a marked increase of prostaglandins.
Apart from these, there are some other animal models, which are comparatively less used videlicet formaldehyde induced arthritis, cotton pellet induced granuloma, subcutaneous air pouch, pristine induced arthritis, etc.
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Written by Shikha Sharma and Debasis Sahu