3.2.1. Animal Models

Animal models of RA are divided into immunization and transfer models [143]. The former is induced by active immunization with normal joint constituents, such as type II collagen (CII) or proteoglycan, and encompass both innate and adaptive immune responses. The collagen-induced arthritis (CIA) model, the most commonly used animal model of RA, is induced by intradermal injection of heterologous CII in complete Freund's adjuvant (CFA) into the tail [144], leading to an autoimmune response in the joint, such as increased infiltration of circulating immune cells, chronic inflammation, and tissue damage, mimicking human RA [145]. Inflammatory polyarthritis is induced in specific mouse strains, such as DBA1 and C57BL/6. In antigen-induced arthritis (AIA), injection of methylated bovine serum albumin (mBSA) mixed with CFA into the base of the tail or knee joint of mice or rats leads to monoarticular arthritis. The subsequent pathology includes immune complex-mediated inflammation followed by articular T cell-mediated responses [146]. On the

other hand, the transfer model is induced by injection of pathogenic autoantibodies or serum, and recapitulates the effector phase of RA. The collagen antibody-induced arthritis (CAIA) model is induced by injecting a cocktail of anti-CII antibodies and lipopolysaccharide (LPS), and is applicable independent of mouse strain or genotype [147]. The K/BxN serum-transfer arthritis model is induced by injecting anti-glucose-6-phosphate isomerase (anti-GPI)-positive serum from K/BxN mice into commonly used mouse strains, leading to pathological changes resembling human RA. Both models circumvent the induction phase of RA, and lead to joint inflammation and destruction of articular cartilage as well as elevated inflammatory markers in serum. In addition, a variety of genetically modified knockout or transgenic mice, such as IL-1 receptor antagonist knockout (IL-1RA-KO), IL-6 receptor (IL-6R) knock-in, and TNF-α transgenic (Tg) mice, were used to study the influence of molecular mediators in inflammation and to test the efficacy of novel therapeutics [143,144,148–151].
