Animal models of rheumatoid arthritis and their relevance to human disease
Introduction
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that affects approximately 1% of the population worldwide. Even after decades of research, our understanding of the pathogenesis of the disease and the underlying mechanisms remains rudimentary. Clues to the etiology of RA reside in the preclinical stage where the initial triggering and induction events leading to disease take place. Unfortunately, this phase of human RA is not readily accessible to investigation and therefore remains speculative. The spectrum and disease progression of RA is governed by multiple factors including immune, genetic and environmental factors [1], [2]. In patients with clinically evident disease, RA is readily diagnosed by joint involvement and indices of immune activation and inflammation, however it remains a clinical challenge for Rheumatologists to effectively treat and manage the disease. Multiple components of immunity and inflammation play a role in established disease including T and B lymphocytes, neutrophils and monocytes, and vascular endothelium. Treatment thus typically requires multi-drug therapy. Therefore, a better understanding of the immune and genetic mechanisms during the early phases of RA is critical to the development of novel therapies that may one day lead to a cure of the disease.
The significance of understanding the mechanism of RA is exemplified by the recently developed anti-TNF blockade therapy, which has raised the bar for therapeutic effectiveness in the management of patients. Yet, the relative resistance of RA to various immunotherapeutic strategies remains an enigma and therefore a challenge to both basic scientists and Rheumatologists [2], [3], [4]. Rodent models of RA serve as valuable tools to investigate the underlying mechanisms at early, intermediate and late stages of RA [5], [6], [7]. With the recent advances in molecular biology, immunology, bioinformatics, and drug designing techniques, the possibility of developing novel therapies for RA and other inflammatory diseases is all the more promising.
The concern that no two arthritis models are alike and none is exactly like human RA, makes it all the more important to understand these models given the clinical observation that no two RA patients are exactly alike, and the etiologic stimulus (or stimuli) is unknown. This review encompasses various rodent models of RA that are used to understand the pathogenesis and pathophysiology of RA, and for the evaluation of therapies. Special emphasis has been placed on streptococcal cell wall (SCW) arthritis in rats and collagen-induced arthritis (CIA) in mice, two widely used animal models. The numerous models of RA available to-date have contributed to our understanding of the role of MHC and non-MHC genes, cell lineages involved, cell surface receptors, cytokines and chemokines, and vascular adhesion molecules that are involved in immunologic and inflammatory process leading to arthritis. The contributions and limitations of animal models are discussed in relation to human RA.
Section snippets
Animal models of rheumatoid arthritis
Rodent models of RA have been developed in both rats and mice. Other species have also been used over the years, however rodent models are most common, due to cost, homogeneity of the genetic background, and in mice, the capacity to use genetically modified strains. Most RA in animals is produced by treatment with an inducing agent, and even “spontaneous” models can be considered induced since they develop by the introduction or deletion of specific genes in animals with the proper immunologic
Mouse models of rheumatoid arthritis
Numerous approaches have been developed to induce arthritis in mice by immunization or injection. Genetically modified mouse strains have provided other, usually spontaneous, models of arthritis and are reviewed below. Collagen-induced arthritis is the best known induced model and is perhaps the easiest to appreciate conceptually, as it involves immunization with a known cartilage component. This model is discussed in more detail below. Antigen-induced arthritis (AIA) is another model, induced
Understanding mechanisms of arthritis from animal models
The immune mechanisms in the pathogenesis of RA have been difficult to understand given the inability to identify an initiating event. The putative mechanisms have evolved as our immunologic knowledge has expanded, and have varied with the trends in immunology. Throughout these developments in understanding human RA, animal models have played a key role in defining mechanisms and establishing some common features. They have also often challenged our cherished beliefs in what factors are
Concluding remarks
In this review we have attempted to cover several important animal models of RA that are widely used or provide important insights. In spite of decades of research, RA still remains a disease of unknown etiology and a complex disease without a single treatment plan. Of the many available animal models, CIA, SCW and more recently the K/BxN model have proven very useful in understanding some of the mechanisms involved. The spontaneous models of RA also appear to be useful, however, lack of a
Acknowledgements
We thank Dr. Shu Man Fu, Division of Rheumatology, University of Virginia Health System at Charlottesville; Dr. Robert Wolf, Rheumatology, Veterans Affairs Hospital, Shreveport, Louisiana; and Dr. Mathew Grisham, Department of Cellular and Molecular Physiology, LSUHSC, Louisiana, for fruitful discussions on this topic. Additional thanks are due to National Institutes of Health for grant support (NIH R01-AR-46976).
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