Open Access

Characterization of a novel and spontaneous mouse model of inflammatory arthritis

Arthritis Research & Therapy201113:126

DOI: 10.1186/ar3434

Published: 16 September 2011

Abstract

Arthritis is a heterogeneous disease comprising a group of inflammatory and non-inflammatory conditions that can cause pain, stiffness and swelling in the joints. Mouse models of rheumatoid arthritis (RA) have been critical for identifying genetic and cellular mechanisms of RA and several new mouse models have been produced. Various methods have been applied to induce experimental models of arthritis in animals that would provide important insights into the etiopathogenetic mechanisms of human RA. Adipue and colleagues recently discovered that mice in their breeding colony spontaneously developed inflamed joints reminiscent of RA and may, therefore, have found a new model to examine pathogenic mechanisms and test new treatments for this human inflammatory disease.

Mouse model of rheumatoid arthritis

Adipue and colleagues [1] have characterized the novel IIJ (inherited inflamed joints) mouse strain, a new murine model of inflammatory, possibly autoimmune, arthritis that is similar both histologically and serologically to human rheumatoid arthritis (RA) and other murine models of autoimmune arthritis [1]. RA is a chronic and progressive inflammatory disorder characterized by synovitis and severe joint destruction. The pathogenesis of RA is a complex process, involving synovial cell proliferation and fibrosis, pannus formation, and cartilage and bone erosion [2]. Rodent models of RA have been used extensively to evaluate potential new therapeutic agents.

Arthritis in the mouse can be induced, can occur spontaneously in some inbred strains, or can result from single gene mutations (Table 1). Induced murine arthritis models include immunization with type II collagen (DBA/1LacJ), or treatment with pristane (BALB/c), thymocytes (C3H/He), mycoplasma (CBA), or a high fat diet (C57BL). Spontaneous models can be grouped according to their origin: development of autoimmune-prone strains by selective mixing of previously existing inbred strains (for example, the MRL/lpr strain [3]); targeted gene manipulation (for example, the TCR trans-genic K/BxN model [4], TNF-α overexpression models [5], the IL-1Ra knock-out model [6], and the gp130Y759F-induced mutant); and identification of spontaneous mutants from breeding colonies (for example, SKG mice with a point mutation in Zap-70 [7]).
Table 1

Animal models of arthritis

Model

Abbreviation

Species

Feature

Induced models

   

   Non-specific immune stimuli

   

Adjuvant-induced arthritis

AA

Lewis rat

Autoimmune

Oil-induced arthritis

OIA

DA rat

Autoimmune

Pristane-induced arthritis

PIA

DA ra

Autoimmune

   Cartilage directed autoimmunity

   

Collagen-induced arthritis

CIA

DBA mouse

CII AI

Proteoglycan-induced arthritis

PGIA

Balb/c mouse

PG AI

   Infectious agents/exogenous triggers

   

Streptococcal cell wall arthritis

SCW-A

Lewis rat

Persistent bacteria AI

Flare

SCW-F

Mouse

Th17

Antigen-induced arthritis

AIA

Rabbit, mouse

Persistent antigen

Flare

AIA-F

Mouse

Th17

Transgenic spontaneous models

   

   HTLV-induced arthritis

HTLV

Mouse

Viral tax antigen

   KRN arthritis

KRN

K/BxN mouse

GPI AI

   SKG arthritis

SKG

Mouse

ZAP-70 T cell defect

   GP130 arthritis

GP130

Mouse

STAT3, T cell defect

   TNF transgenic arthritis

TNFtg

Mouse

TNF overexpression

   IL-1ra transgenic arthritis

IL-1ra-/-

Balb/c mouse

Autoimmune T cells

   IL-1 transgenic arthritis

IL-1tg

Mouse

IL-1 overexpression

Immune complex models

   

   Collagen type II

CAIA

DBA mouse

Mouse CII antibody

   KRN serum

GPI

Balb/c mouse

Mouse GPI antibody

   Poly-L-lysine-lysozyme

PLL-L

DBA mouse

Cationic antigen

New animal model

   

   Spontaneous

   

Inherited inflamed joints strain

IIJ

Arthritic male mouse crossed with SJL/J females

Autoimmune arthritis (for understanding the female bias)

AI, autoimmunity; CII, collagen type II; GPI, glucose-6-phosphate isomerase; HTLV, human T-lymphotropic virus; IL, interleukin; KRN, C57Bl/6 mice carrying the KRN transgene heterozygously; PG, proteoglycan; SKG, SKG strain, derived from closed breeding colony of BALB/c mice, spontaneously develops chronic arthritis; TNF, tumor necrosis factor.

Despite the existence of all of these models, it is well known that no animal model represents RA in its entirety. In addition, clinical manifestations are different between different strains of mice, even if the same induction protocol is employed, and some of the strains are even selected because of their susceptibility to auto-immunity. Even though it is improbable that a single animal model could assume and reproduce human disease in its entirety and consistently, animal models have allowed us to understand common principles of the induction and persistence of inflammatory processes and the pathways involved in cartilage and bone erosion and, therefore, have helped identify new therapeutic targets (Table 2).
Table 2

Drugs used to treat arthritis

Type of drug

Name of drug

Use

Drugs that affect symptoms of the disease (analgesics)

Acetaminophen

Aspirin

Relieves pain

Reduces inflammation and relieves pain

Oral nonsteroidal anti-inflammatory drugs (NSAIDs)

Diclofenac

Diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin

Reduces inflammation and relieves pain

All NSAIDs treat the symptoms and decrease inflammation but do not alter the course of the disease

COX-2 inhibitors

Celecoxib, valdecoxib

Reduces inflammation and relieves pain

Narcotic/analgesics

Propoxyphene

Tramadol

Relieves pain

Relieves pain

Corticosteroids

Methylprednisolone, prednisone, injectable corticosteroids

Suppresses inflammation in severe organ disease or life-threatening disease

Disease-modifying antirheumatic drugs (DMARDs)a

Auranofin (oral gold), cyclosporine, gold salts (injectable), hydroxychloroquine, leflunomide, methotrexate, penicillamine, sulfasalazine

All DMARDs can slow progression of joint damage as well as gradually decrease pain and swelling

Biologics

  

   Anti-TNF compounds

Adalimumab, etanercept, infliximab, certolizumab, golimumab

Suppresses inflammation and inhibit the progress of joint damage

   IL-1 inhibitor

Anakinra

Treats moderate to severe RA in people who do not respond to DMARDs

   B-cell-depleting agent

Rituximab

Treats RA unresponsive to TNF inhibitors

   T-cell co-stimulation antagonist

Abatacept

Treats RA unresponsive to DMARD therapy

   IL-6 antagonist

Tocilizumab

Treats RA unresponsive to TNF inhibitors

COX, cyclooxygenase; DMARD, disease-modifying anti-rheumatic drug; IL, interleukin; RA, rheumatoid arthritis; TNF, tumor necrosis factor.

Characterization of a novel and spontaneous mouse model of inflammatory arthritis

Adipue and colleagues [1] describe a new strain of mouse that spontaneously develops a chronic inflammatory, possibly autoimmune, arthritis that shares many similarities with human RA and other mouse models of arthritis. The authors point out that arthritis incidence in IIJ mice also displays the sex bias common to many complex autoimmune diseases such as RA, multiple sclerosis, and systemic lupus erythematosus [8]. The sex bias appears to be specific for the arthritis phenotype since the incidence of typhlocolitis was similar between male and female IIJ mice. As most models reach 100% incidence in both sexes, no other spontaneous mouse model of arthritis has displayed such a sex bias, although more severe arthritis in females has been reported for both the SKG [7] and gp130Y759F models [9]. A female bias in incidence was also observed in collagen-induced arthritis in humanized HLA-DR4-transgenic mice [10] and was attributed to both hyperactive B cells and HLA-DR4 restricted antigen presentation in female mice and increased numbers of T and B regulatory cells in male mice [11]. In particular, Adipue and colleagues emphasize that the histopathology in IIJ mice is similar to that described in previously published mouse models of autoimmune arthritis [7, 9]. In addition, the predominantly neutrophilic and lymphocytic infiltration into the inflamed IIJ joints parallels the large numbers of neutrophils and T cells present in the inflamed synovial fluid of RA patients [12]. Finally, the IIJ mice also share serological similarities with RA and some other mouse models.

Conclusion

Adipue and colleagues have identified the IIJ strain as a new murine model of inflammatory, possibly autoimmune, arthritis. The IIJ strain is similar both histologically and serologically to RA and other murine models of autoimmune arthritis. Moreover, the increased incidence of arthritis in female IIJ mice makes it a potentially important model to study the underlying causes of sex bias in autoimmunity.

Abbreviations

IIJ: 

inherited inflamed joint

IL: 

interleukin

RA: 

rheumatoid arthritis.

Declarations

Authors’ Affiliations

(1)
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario, Via C. Valeria

References

  1. Adipue IA, Wilcox JT, King C, Rice CA, Shaum KM, Suard CM, Brink ET, Miller SD, McMahon EJ: Characterization of a novel and spontaneous mouse model of inflammatory arthritis. Arthritis Res Ther. 2011, 13: R114-10.1186/ar3399.PubMed CentralView ArticlePubMed
  2. Di Paola R, Cuzzocrea S: Predictivity and sensitivity of animal models of arthritis. Autoimmun Rev. 2008, 8: 73-75. 10.1016/j.autrev.2008.07.029.View ArticlePubMed
  3. Kamogawa J, Terada M, Mizuki S, Nishihara M, Yamamoto H, Mori S, Abe Y, Morimoto K, Nakatsuru S, Nakamura Y, Nose M: Arthritis in MRL/lpr mice is under the control of multiple gene loci with an allelic combination derived from the original inbred strains. Arthritis Rheum. 2002, 46: 1067-1074. 10.1002/art.10193.View ArticlePubMed
  4. Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C, Mathis D: Organ-specific disease provoked by systemic autoimmunity. Cell. 1996, 87: 811-822. 10.1016/S0092-8674(00)81989-3.View ArticlePubMed
  5. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G: Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991, 10: 4025-4031.PubMed CentralPubMed
  6. Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y: Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med. 2000, 191: 313-320. 10.1084/jem.191.2.313.PubMed CentralView ArticlePubMed
  7. Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S: Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003, 426: 454-460. 10.1038/nature02119.View ArticlePubMed
  8. Lleo A, Battezzati PM, Selmi C, Gershwin ME, Podda M: Is autoimmunity a matter of sex?. Autoimmun Rev. 2008, 7: 626-630. 10.1016/j.autrev.2008.06.009.View ArticlePubMed
  9. Atsumi T, Ishihara K, Kamimura D, Ikushima H, Ohtani T, Hirota S, Kobayashi H, Park SJ, Saeki Y, Kitamura Y, Hirano T: A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J Exp Med. 2002, 196: 979-990. 10.1084/jem.20020619.PubMed CentralView ArticlePubMed
  10. Taneja V, Behrens M, Mangalam A, Griffiths MM, Luthra HS, David CS: New humanized HLA-DR4-transgenic mice that mimic the sex bias of rheumatoid arthritis. Arthritis Rheum. 2007, 56: 69-78. 10.1002/art.22213.View ArticlePubMed
  11. Behrens M, Trejo T, Luthra H, Griffiths M, David CS, Taneja V: Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice. J Autoimmun. 2010, 35: 1-9. 10.1016/j.jaut.2009.12.007.PubMed CentralView ArticlePubMed
  12. Firestein GS: Evolving concepts of rheumatoid arthritis. Nature. 2003, 423: 356-361. 10.1038/nature01661.View ArticlePubMed

Copyright

© BioMed Central Ltd 2011