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Rodent Models and Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an inflammatory disease that attacks the joints and has plagued middle-aged and elderly generations for centuries. Despite ongoing research efforts, the cause of RA remains unknown, but it is characterized by aggressive synovial hyperplasia and inflammation. Without treatment, this leads to the destruction of joint cartilage and bone. Researchers and medical professionals have attempted to alleviate the pain and discomfort associated with arthritis for many years and, more recently, rodent models have benefited the investigation of treating this condition.

Approximately 1% of the adult population will get RA, with more women than men being affected. RA is a chronic disease that leads to the progressive destruction of joints, causing gradually increasing disability. While RA typically affects the hands and feet, it can also affect larger joints, and in rare case, other tissues such as the skin, eyes, lungs, and blood vessels.

Treatment for RA traditionally relied on anti-inflammatory drugs, including NSAIDS and a category of drugs known as DMARDs (disease modifying anti-rheumatic drugs), a mixture of different drug types of which the most commonly used is methotrexate, a cytotoxic agent commonly used in cancer therapy. Other DMARDs include leflunomide (an anti-inflammatory), sulfasalazine, cyclophosphamide (a cytotoxic), azothiaprin, and cyclosporine (immunosuppressives) and hydroxychloroquin.

Recent drug development for RA has focused on modulation of the immune system through the use of antibodies to block specific cytokines and their receptors, particularly TNF-a and CD-20, but also CD-80, CCR-1, CCR2, CCR-5, IL-12, IL-23, IL-15, IL-1. In addition to cytokine and chemokine targeting, other mechanisms for cellular communication have been targeted as well, including prostaglandins, nitric oxide, and oxygen free radical scavengers, along with the intracellular signaling pathways used by the various different communication methods.

Rodent models of RA have focused on generating an auto-immune response leading to joint inflammation that mimics human RA. Commonly used models include adjuvant induced arthritis (AIA), type-II collagen and glucose-6-phospate isomerase (G6PI).

Animals immunized with these agents of these proteins develop inflammation of the paws after 2-4 weeks. The inflammation of the paws can be evaluate using a simple scoring system, or can be evaluated histologically or via imaging. Imaging arthritis in mice relies on fluorescent labels that target the matrix metalloproteinases. Matrix metalloproteinases (MMPs) are enzymes that remodel the extracellular matrix that exists between all cells and is a critical component of collagen. Elevations in MMP activity levels are a very early stage in the remodeling of collagen in joints affected by  RA, and can be detected before any signs of arthritis are visible to the naked eye.

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Categories: Inflammatory diseases

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