Animal models of arthritis: Part 1: Comparison
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Animal models play a pivotal role in advancing our understanding of rheumatoid arthritis (RA), a complex autoimmune disease. This entry explores four key animal models used in RA research: Streptococcal Cell Wall-Induced Arthritis (SCWIA), Collagen-Induced Arthritis (CIA), Collagen Antibody-Induced Arthritis (CAIA), and Proteoglycan-Induced Arthritis (PGIA). SCWIA closely mimics human RA, involving bacterial cell wall peptidoglycans and toll-like receptor (TLR)-4 activation. CIA replicates RA's clinical, histological, and immunological aspects, with a prominent role for B cells. CAIA, characterized by rapid onset and independence from MHC alleles, lacks T and B cell involvement. PGIA, specific to BALB/c mice, closely resembles human RA in various aspects. Each model offers unique advantages and limitations, catering to specific research objectives. Together, they enhance our comprehension of RA pathogenesis and potential therapeutic interventions, guiding researchers on their quest to unravel the intricacies of this debilitating autoimmune disorder.

  • rheumatoid arthritis
  • animal models
  • Streptococcal Cell Wall-Induced Arthritis
  • Collagen-Induced Arthritis
  • Collagen Antibody-Induced Arthritis
  • Proteoglycan-Induced Arthritis

Introduction

Mice and rats, those diminutive yet biologically intricate creatures, serve as invaluable sentinels in the labyrinthine world of human disease exploration. Among the myriad of ailments they illuminate, rheumatoid arthritis (RA) stands as a prominent domain. These unassuming creatures proffer an array of advantages to discerning researchers: their straightforward maintenance, abbreviated reproductive cycles, genetic semblance to Homo sapiens, and genetic tweakability, just to name a few [1]. In this intricate narrative of RA, wherein genetic susceptibility, environmental enigmas, and the fervent proclamations of inflammatory cytokines such as TNF-α and interleukins orchestrate the dramatic crescendo [2], the quest for efficacious treatments unfolds. The present arsenal, replete with stalwart soldiers like disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs), has indomitably confronted RA's onerous onslaught. Yet, beneath their valorous veneer, lurk the lurking shadows of pernicious side effects that cast long shadows over long-term usage.

But behold, the wisdom of the ages, encapsulated in the treasures of Traditional Chinese Medicines (TCM), beckons as a siren's song amidst these tumultuous waters. Within their ancient pharmacopeias lie promises of respite, as they deftly navigate the labyrinthine corridors of RA with efficacy, minimal side effects, and a diverse array of therapeutic modalities. However, an enigmatic veil shrouds their potential, for the validation of TCM efficacy in the crucible of animal models remains an unfolding narrative, awaiting its denouement  [1][2].

The emergence of animal models from the crucible of scientific ingenuity to peer into the secrets of RA's pathogenesis. Through their lens, we may unravel the enigma of genetic susceptibility, demystify the capricious influences of environmental factors, and decode the arcane language of inflammatory cytokines. As we navigate the labyrinthine passages of these models, we endeavor to provide you, the discerning reader, with an illuminating compendium. Armed with knowledge, you may tread confidently, selecting the most fitting model to serve as your guide on your research journey.

Streptococcal Cell Wall-Induced Arthritis (SCWIA)

Streptococcal cell wall-induced arthritis (SCWIA) is a model that closely mimics human RA. Bacterial cell wall peptidoglycans possess pro-inflammatory properties relevant to rheumatic diseases. They can trigger acute inflammation by directly activating the complement system. SCW-specific antibody responses and cartilage and bone destruction depend on toll-like receptor (TLR)-4, indicating a shift from innate to adaptive immune involvement during the chronic phase of the disease [3][4].

SCWIA clinically, histologically, and radiologically resembles RA in humans. It manifests as symmetrical peripheral joint involvement, differentiating it from other models like AIA. SCWIA and AIA, while similar, exhibit differences in the clinical course, with AIA being monophasic, while SCWIA is biphasic [5][6][7].

The development of SCWIA is influenced by various factors, including infection and stress. A pathogen-free environment and widely spaced housing are crucial for successfully inducing SCWIA. Genetic and immunological mechanisms also play a role in determining susceptibility to arthritis in this model. Incidence varies between rat strains, and hormonal factors, sex-linked effects, and host genetic background are important contributors to susceptibility [8][9].

Collagen-Induced Arthritis (CIA)

Collagen-induced arthritis (CIA) is a widely used model for studying RA. It is induced by immunizing animals with collagen type II (CII), the main component of articular cartilage. After immunization, animals develop autoimmune-mediated polyarthritis that closely resembles human RA in clinical, histological, radiological, and immunological aspects.

In CIA, B cells play a significant role, and B cell-deficient mice do not develop type II CIA. The immune response to CII involves stimulating collagen-specific T and B cells, leading to the production of high titers of antibodies specific to immunogens and autoantigens [55][10]. Various type II collagens from different species can induce CIA in susceptible mouse strains, with differences observed between mouse strains and their sensitivity to these collagens [57][11]. The rat model of CIA offers advantages, with some rat strains, such as Wistar rats, exhibiting a high incidence of severe arthritis [18][12].

Collagen Antibody-Induced Arthritis (CAIA)

Collagen antibody-induced arthritis (CAIA) is induced by administering monoclonal antibodies targeting CII. CAIA shares several characteristics with CIA, including macrophage infiltration and inflammatory cell presence in joints. However, it does not involve T and B cell responses, making it distinct from CIA.

CAIA is a rapid model, with acute joint inflammation typically appearing 24-48 hours after immunization  [1013]. It can be induced in nearly all mouse strains and is independent of MHC alleles, differentiating it from CIA, which is highly susceptible to specific MHC alleles [1114]. CAIA allows researchers to study common mechanisms involving antibody-mediated diseases and screen candidate drugs for controlling joint inflammation.

Proteoglycan-Induced Arthritis (PGIA)

Proteoglycan-induced arthritis (PGIA) is specifically induced in BALB/c mice. PGIA closely resembles human RA in clinical, histological, genetic, and immunological aspects. This model is induced by immunizing mice with deglycosylated human or canine chondroprotein polysaccharide [1215][1316]. Notably, no other mouse strains or laboratory animals, including rats, hamsters, guinea pigs, rabbits, and dogs, are sensitive to PGIA.

PGIA in BALB/c mice exhibits a long development phase, with arthritis appearing approximately 28 days after immunization. The disease onset involves swelling, redness, and edema of synovial and periarticular tissues, followed by massive cell proliferation. The mononuclear cell inflammatory reaction eventually leads to complete degradation of articular cartilage, bone erosion, and severely deformed peripheral joints  [1417]. The proximal intervertebral discs of the lumbar spine and tail also become inflamed and degenerate.

The development of PGIA is based on cross-reactive immune responses between immune allogeneic and autologous proteoglycans (PGs), involving autoreactive T cells and autoantibodies against murine PG. These autoantibodies enter joints and bind to cartilage PG, forming IgG immune complexes (ICs). The FcγR is associated with the development of PGIA [1518][1619][1720].

Conclusion

In the ever-evolving realm of rheumatoid arthritis research, these animal models stand as indispensable companions, each possessing its unique strengths and limitations. Researchers, akin to discerning travelers, carefully choose their paths, guided by the compass of their specific research objectives and the facets of RA they seek to replicate. With every selection, a deliberate balance is struck between the model's fidelity to the human condition and the practical advantages it affords. These models, as a collective, represent the quiver from which researchers draw their arrows of insight. Together, they form the cornerstone of our expanding comprehension of RA's intricate pathogenesis. Through their intricate tapestry of genetic predisposition, environmental interactions, and the symphony of inflammatory cascades, these models unveil the mysteries that enshroud this debilitating condition. Moreover, they are not just instruments of understanding but potent catalysts for change. As we navigate the labyrinth of RA research, these models serve as beacons, guiding us toward potential therapeutic interventions. They provide the framework upon which innovative treatments may be devised, offering hope for those afflicted by the burdensome mantle of rheumatoid arthritis.

References

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  2. Terao, C., Raychaudhuri, S., & Gregersen, P. K. (2016). Recent advances in defining the genetic basis of rheumatoid arthritis. Annual review of genomics and human genetics, 17, 273-301.
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  4. Abdollahi-Roodsaz S, Joosten LA, Helsen MM, Walgreen B, van Lent PL, van den Bersselaar LA, Koenders MI, van den Berg WB. Shift from toll-like receptor 2 (TLR-2) toward TLR-4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR-4-mediated interleukin-17 production. Arthritis Rheum. 2008 Dec;58(12):3753-64. doi: 10.1002/art.24127. PMID: 19035506.
  5. Perruche, S., Saas, P., & Chen, W. (2009). Apoptotic cell-mediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T-cell increase: a potential cell-based therapy?. Arthritis research & therapy, 11(4), 1-8.
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  7. Arntz, O. J., Geurts, J., Veenbergen, S., Bennink, M. B., van den Brand, B. T., Abdollahi-Roodsaz, S., ... & van de Loo, F. A. (2010). A crucial role for tumor necrosis factor receptor 1 in synovial lining cells and the reticuloendothelial system in mediating experimental arthritis. Arthritis research & therapy, 12, 1-11.
  8. Sternberg, E. M., Young 3rd, W. S., Bernardini, R., Calogero, A. E., Chrousos, G. P., Gold, P. W., & Wilder, R. L. (1989). A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proceedings of the National Academy of Sciences, 86(12), 4771-4775.
  9. Sternberg, E. M., Hill, J. M., Chrousos, G. P., Kamilaris, T., Listwak, S. J., Gold, P. W., & Wilder, R. L. (1989). Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proceedings of the National Academy of Sciences, 86(7), 2374-2378.
  10. Nandakumar, K. S., & Holmdahl, R. (2007). Collagen antibody induced arthritis. Arthritis Research: Methods and Protocols Volume 2, 215-223.Svensson, Jirholt, Holmdahl, & Jansson. (1998). B cell‐deficient mice do not develop type II collagen‐induced arthritis (CIA). Clinical & Experimental Immunology, 111(3), 521-526.
  11. Nandakumar KS, Bäcklund J, Vestberg M, Holmdahl R. Collagen type II (CII)-specific antibodies induce arthritis in the absence of T or B cells but the arthritis progression is enhanced by CII-reactive T cells. Arthritis Res Ther. 2004;6(6):R544-50. doi: 10.1186/ar1217. Epub 2004 Sep 23. PMID: 15535832; PMCID: PMC1064861.Donate, P. B., Fornari, T. A., Junta, C. M., Magalhães, D. A., Macedo, C., Cunha, T. M., ... & Passos, G. A. (2011). Collagen induced arthritis (CIA) in mice features regulatory transcriptional network connecting major histocompatibility complex (MHC H2) with autoantigen genes in the thymus. Immunobiology, 216(5), 591-603.
  12. Glant, T. T., Radacs, M., Nagyeri, G., Olasz, K., Laszlo, A., Boldizsar, F., ... & Mikecz, K. (2011). Proteoglycan‐induced arthritis and recombinant human proteoglycan aggrecan G1 domain–induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis. Arthritis & rheumatism, 63(5), 1312-1321.Song, H. P., Li, X., Yu, R., Zeng, G., Yuan, Z. Y., Wang, W., ... & Cai, X. (2015). Phenotypic characterization of type II collagen-induced arthritis in Wistar rats. Experimental and Therapeutic Medicine, 10(4), 1483-1488.
  13. Farkas, B., Boldizsar, F., Tarjanyi, O., Laszlo, A., Lin, S. M., Hutas, G., ... & Glant, T. T. (2009). BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance. Arthritis research & therapy, 11, 1-13.Nandakumar, K. S., & Holmdahl, R. (2007). Collagen antibody induced arthritis. Arthritis Research: Methods and Protocols Volume 2, 215-223.
  14. Szántó, S., Bárdos, T., Gál, I., Glant, T. T., & Mikecz, K. (2004). Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 50(9), 3012-3022.Nandakumar KS, Bäcklund J, Vestberg M, Holmdahl R. Collagen type II (CII)-specific antibodies induce arthritis in the absence of T or B cells but the arthritis progression is enhanced by CII-reactive T cells. Arthritis Res Ther. 2004;6(6):R544-50. doi: 10.1186/ar1217. Epub 2004 Sep 23. PMID: 15535832; PMCID: PMC1064861.
  15. Doodes, P. D., Cao, Y., Hamel, K. M., Wang, Y., Rodeghero, R. L., Mikecz, K., ... & Finnegan, A. (2010). IFN-γ regulates the requirement for IL-17 in proteoglycan-induced arthritis. The journal of immunology, 184(3), 1552-1559.Glant, T. T., Radacs, M., Nagyeri, G., Olasz, K., Laszlo, A., Boldizsar, F., ... & Mikecz, K. (2011). Proteoglycan‐induced arthritis and recombinant human proteoglycan aggrecan G1 domain–induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis. Arthritis & rheumatism, 63(5), 1312-1321.
  16. Kaplan, C. D., O’Neill, S. K., Koreny, T., Czipri, M., & Finnegan, A. (2002). Development of inflammation in proteoglycan-induced arthritis is dependent on FcγR regulation of the cytokine/chemokine environment. The Journal of Immunology, 169(10), 5851-5859.Farkas, B., Boldizsar, F., Tarjanyi, O., Laszlo, A., Lin, S. M., Hutas, G., ... & Glant, T. T. (2009). BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance. Arthritis research & therapy, 11, 1-13.
  17. Olalekan, S. A., Cao, Y., Hamel, K. M., & Finnegan, A. (2015). B cells expressing IFN‐γ suppress Treg‐cell differentiation and promote autoimmune experimental arthritis. European journal of immunology, 45(4), 988-998.Szántó, S., Bárdos, T., Gál, I., Glant, T. T., & Mikecz, K. (2004). Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 50(9), 3012-3022.
  18. Doodes, P. D., Cao, Y., Hamel, K. M., Wang, Y., Rodeghero, R. L., Mikecz, K., ... & Finnegan, A. (2010). IFN-γ regulates the requirement for IL-17 in proteoglycan-induced arthritis. The journal of immunology, 184(3), 1552-1559.
  19. Kaplan, C. D., O’Neill, S. K., Koreny, T., Czipri, M., & Finnegan, A. (2002). Development of inflammation in proteoglycan-induced arthritis is dependent on FcγR regulation of the cytokine/chemokine environment. The Journal of Immunology, 169(10), 5851-5859.
  20. Olalekan, S. A., Cao, Y., Hamel, K. M., & Finnegan, A. (2015). B cells expressing IFN‐γ suppress Treg‐cell differentiation and promote autoimmune experimental arthritis. European journal of immunology, 45(4), 988-998.
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