Experimental Animal Models Of Arthritis Research Articles

GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium

Emerging preclinical and clinical evidence reveals a critical role for the cholinergic anti-inflammatory pathway (CAP) in mediating rheumatoid arthritis (RA). Activation of CAP via vagus nerve stimulation or alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonists has previously been shown to significantly reduce inflammation and improve outcomes in animal models of experimental arthritis. In this study, we sought to determine the protective mechanism of CAP on inflammatory arthritis, specifically RA, by using a selective α7nAChR agonist, GTS-21, to examine the role of CAP in the recruitment of monocytes/macrophages into the synovium in a collagen-induced arthritis (CIA) mouse model.We found that GTS-21 ameliorated systemic and local synovial inflammation, thereby reducing synovial macrophage infiltration in CIA mice. Using in vivo imaging, we further demonstrated that GTS-21 suppressed the trafficking of monocytes into inflamed joints, while our in vitro Transwell assay data confirmed that GTS-21 reduced the migratory ability of monocytes. In addition, we found that GTS-21 reduced the number of peripheral inflammatory monocytes and down-regulated expression of the chemokines CCR2 and CCR5 on monocytes and CCL2 in the paw tissue. GTS-21 also mediated the expression levels of the adhesion molecules LFA-1 and VLA-4 on monocytes and VCAM-1 in the paw tissue, thereby blocking monocyte adhesion to the extracellular matrix.Together, our data demonstrate that GTS-21 alleviates arthritis by inhibiting peripheral monocyte trafficking into the synovium. Our findings describe a novel mechanism through which the cholinergic signaling pathway can reduce synovial inflammation in RA patients.

Possibilities for preventive treatment in rheumatoid arthritis? Lessons from experimental animal models of arthritis: a systematic literature review and meta-analysis

ObjectiveCurrent research in rheumatoid arthritis focuses on preclinical disease phases as it is hypothesised that early preclinical treatment might prevent progression to full-blown disease. Since performance of studies in prearthritis...

The role of very late antigen-1 in immune-mediated inflammation

The α1β1 integrin, also known as “very late antigen” (VLA)-1, is normally expressed on mesenchymal cells, some epithelial cells, activated T cells, and macrophages, and interacts, via the I-domain of the extracellular domain of the α1 subunit, with collagen molecules in the extracellular matrix (ECM). By “outside–in” transmembranal signaling to the interior of the cell, it mediates adhesion, migration, proliferation, remodeling of the ECM, and cytokine secretion by endothelial cells, mesangial cells, fibroblasts, and immunocytes. Importantly, its expressions and functions are enhanced by inflammatory cytokines including interferon (IFN)γ and tumor necrosis factor (TNF)α, thus augmenting angiogenesis and fibrosis linked, in particular, to inflammation. Moreover, within the immune system, VLA-1 marks effector memory CD4+ and CD8+ T cells that are retained in extralymphatic tissues by interactions of the integrin with collagen and produce high levels of IFNγ. Thus, immune-mediated inflammation in vivo is inhibited by blockade of the VLA-1-collagen interaction in experimental animal models of arthritis, colitis, nephritis, and graft versus host disease (GVHD), suggesting that inhibiting the interaction of the α1 I-domain with its ligands or modulating “outside–in” signaling by VLA-1 would be a useful approach in the human diseases simulated by these experimental models.

Heat shock proteins, inflammation, and cardiovascular disease.

Atherosclerosis and its associated complications, such as coronary artery disease, peripheral vascular disease, and stroke, are the leading causes of morbidity and mortality in all racial groups of most westernized societies. A better understanding of the events that lead to the induction and progression of atherosclerosis and the development of strategies that control these processes would have a significant impact on human health. Atherosclerosis is a chronic inflammatory condition that usually begins at an early age in the absence of lipid accumulation, with fatty streaks composed of lipid-laden macrophages (foam cells) developing at later stages. T lymphocytes, predominantly of the CD4+ phenotype, are associated with the intima layer of the vessel. The inflammatory process at atherogenic sites leads to the production of cytokines and other inflammatory mediators, resulting in cell migration, proliferation, extracellular matrix production, and plaque development.1–3⇓⇓ Monocytes and macrophages appear intimately involved with the development of atherosclerosis; mice with the osteopetrotic ( op ) mutation in the macrophage colony-stimulating factor (M-CSF) gene, which results in a complete absence of M-CSF in the serum and tissues and a marked reduction in the number of circulating monocytes, exhibit significantly less atherosclerosis than control littermates when bred into an apolipoprotein (apo) E–deficient background,.4 The precise role of T and B cells in atherosclerosis remains unclear. Although activated T cells are a dominant feature of atherosclerotic lesions,5,6⇓ studies demonstrating that atherosclerosis can be induced by hypercholesterolemia in mice deficient in T and B cells suggest that these cells are not essential.7–9⇓⇓ However, the cholesterol levels in these studies far exceeded those present in human subjects without any genetic defect, and the findings should therefore be interpreted with caution. Indeed, other evidence indicates that T cells may attenuate atherogenesis by some means, because the elimination of …

Two variables that can be used as pain indices in experimental animal models of arthritis

Since pain is an important symptom in arthritis, useful behavioral indices for pain in experimental arthritis animal models are important tools for investigative work on arthritis. The purpose of this study was to develop simple and quantifiable behavioral tests, which would represent the level of arthritic pain that develops after induction of inflammation in the knee. Two models of knee joint arthritis were produced: (1) KC model—injection of kaolin and carrageenan into the synovial cavity of the knee, and (2) CFA model—injection of complete Freund's adjuvant into the synovial cavity of the knee. The following three variables were measured before and at various times after the induction of arthritis. As an estimate of the degree of edema, the circumference of the knee was measured. As pain indices, (1) the vocalization threshold of compression force applied to the knee joint was measured to represent tenderness of the joint, and (2) the struggle threshold of the knee extension angle was measured to represent a reduction in range of motion in the arthritic joint. A time course study showed that behavioral changes last for at least 1 week for the KC model and at least 2 weeks for the CFA model. Correlation studies showed that all three variables significantly correlated with each other in both the KC and CFA arthritic models. Systemically injected morphine produced a partial reversal of these indices with the expected time course and dose response of a morphine-induced analgesic. It is concluded that two variables, the struggle threshold for knee extension and the vocalization threshold for knee compression, could be used as simple and useful pain indices in experimental models of arthritis.

Complement activation and inhibition in experimental models of arthritis

Complement activation has been implicated as a pathological process in a number of inflammatory and autoimmune disorders including chronic rheumatoid arthritis (RA). Animal models of experimental arthritis have been widely used to investigate the pathogenesis of RA and also in the development of novel therapies. Many of these models are complement-dependent and both incidence and progression of disease can be influenced by complement inhibition. In certain situations, local inhibition is of greater therapeutic benefit than systemic decomplementation. An increasing awareness and availability of a wide range of naturally occurring complement regulatory proteins can now offer a more targeted approach to complement inhibition while the availability of novel engineering strategies has also improved the efficiency of this process. The success of complement inhibition in the experimental models described should offer a novel therapeutic approach to the treatment of human inflammatory arthritis.

Treatment of rheumatoid arthritis with IL-1 inhibitors

Extensive evidence from both in vivo and in vitro experiments indicate that IL-1, a prototypic proinflammatory cytokine, is involved in the mechanisms that lead to progressive joint destruction in RA. IL-1Ra, a member of the IL-1 family, binds IL-1 receptors but does not induce any cellular responses. IL-1Ra competitively inhibits the binding of IL-1 to its cell surface receptors and thus, acts as an endogenous antiinflammatory mediator. However, the results of several studies suggest that a relatively deficient production in IL-1Ra as compared to that of IL-1 in RA synovium may predispose to the perpetuation of chronic inflammation. Systemic administration of IL-1Ra, or local delivery into the joint by gene therapy, in different experimental animal models of arthritis attenuated the severity of the inflammatory response and reduced articular destruction. In addition, treatment of rheumatoid patients with IL-1Ra led to an improvement in different clinical and biological parameters and to a reduction in the radiological signs of joint erosions. Encouraging results also have been reported in both in vitro and in vivo experimental animal models of arthritis through using other strategies designed to block the effects of IL-1 at the level of production, prevent the binding of IL-1 to its cell surface receptors, or interfere with the effects of IL-1 at the post-receptor level.

A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling.

The arthritogenic activities of tumor necrosis factor (TNF) and its p55TNF-receptor (R) have been well documented in experimental animal models of arthritis, and in transgenic mice expressing wild-type or mutant transmembrane human TNF proteins in their joints. In this study we show that chronic inflammatory arthritis also develops in transgenic mice made to overexpress a mutant transmembrane from of the murine TNF protein (muTNF delta 1-12) which is known to utilize efficiently both the p55 and the p75TNFR. Cross-breeding of the transgene into a TNF knockout background did not alter development of disease. Analysis of TNF bioactivity in sera from lipopolysaccharide-stimulated mice or ex vivo macrophage cultures demonstrated that the muTNF delta 1-12 protein accumulates on the cell surface and is not processed to bioactive soluble TNF, indicating that transmembrane TNF is by itself sufficient to mediate pathogenesis of arthritis. Furthermore, using TNFR knockout mice, it is shown that development of transmembrane TNF-mediated arthritis requires the presence of the p55TNFR but is significantly delayed in the absence of the p75TNFR, suggesting a positive cooperation between the two TNFR in the arthritogenic process. These results indicate that blocking the activities of both soluble and transmembrane TNF may be required to effectively neutralize the pathogenic potential of this cytokine in arthritis.

Development and histologic characterizations of an animal model of antigen-induced arthritis of the juvenile rabbit temporomandibular joint.

Children with juvenile rheumatoid arthritis or juvenile chronic arthritis often exhibit temporomandibular joint (TMJ) involvement accompanied by pain, dysfunction, and growth abnormalities. Despite the severe functional and developmental consequences of this disease, its pathogenesis remains poorly understood, but important insights may be provided by a suitable animal model of this disease. The purpose of this study was to develop and histologically characterize a juvenile animal model of antigen-induced arthritis of the TMJ. Arthritis was induced with an intra-articular administration of ovalbumin in previously sensitized 10-week-old male New Zealand white rabbits. Sham-treated and untreated rabbits were used as controls. The TMJs were retrieved en bloc at 5, 10, 15, 35, and 55 days post-challenge for histology and matrix histochemistry. Antigen-treated joints demonstrated severe arthritis, including mononuclear cell infiltration, synovial lining and villous hyperplasia, and pannus formation, as early as 5 days after challenge; the arthritis was maintained up to 55 days post-challenge. A decrease in the area of the TMJ disc that stained positively for glycosaminoglycans was observed throughout the experimental period. Loss of collagen staining was primarily localized to sites at the junction of the synovium with bone and fibrocartilage. The histopathologic features of this model of antigen-induced arthritis of the juvenile rabbit TMJ are similar to those observed previously in adult animal models of experimental arthritis and in human rheumatoid arthritis. This animal model will be useful for understanding the pathogenesis of juvenile rheumatoid arthritis of the TMJ, and for exploring the mechanisms for aberrant craniofacial growth.

Experimental animal models resembling rheumatoid arthritis.

The experimental animal models of arthritis which in certain aspects share similarities to human rheumatoid arthritis are reviewed. Various methods have been applied to induce in animals experimental models of arthritis which would provide important insights into the aetiopathogenetic mechanisms of human RA. Immunological methods and infectious agents induced the most interesting models. The histology of the synovial tissue, regardless of the inducing mechanisms, is similar to the lesions of RA. Yet, none of these experimental models of arthritis reflects all the articular and systemic features, the immunological profile and the genetic factors which characterize the human disease. The animal models of arthritis reported here and the development of new ones may ultimately offer the information necessary for the understanding of the mechanisms involved in the aetiopathogenesis of human rheumatoid disease.

Animal models of rheumatoid arthritis

Experimental animal models of arthritis, including type II collagen-induced arthritis, proteoglycan-induced arthritis, adjuvant arthritis, pristane-induced arthritis, and streptococcal cell wall-induced arthritis have contributed to recent advances in the understanding of the immunopathology of arthritis. The dissection of the T-cell populations regulating the autoimmune response is currently the most active area of investigation. Research into the mechanism underlying the association of specific class II major histocompatibility complex antigens with arthritis has focused attention on the interaction of particular V beta T-cell subsets with antigens presented in context of permissive major histocompatibility complex antigens. Several models indicate that both the structure of the major histocompatibility complex antigen and the T-cell receptor may be critical in the development of autoimmunity, while the MIs antigen system appears to regulate the availability of T cells with self-reactivity specificities. Studies on the role of heat-shock proteins in experimental arthritis have prompted research into the role of gamma/delta T cells in joint disease, while the availability of recombinant cytokines has permitted the direct analysis of soluble factors. In addition to providing basic insights into autoimmune disease, animal models continue to provide the means to test novel experimental approaches to the treatment of rheumatoid arthritis.