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Basic and translational research
A novel mouse model that develops spontaneous arthritis and is predisposed towards atherosclerosis
  1. Shawn Rose1,
  2. Mesut Eren2,
  3. Sheila Murphy2,
  4. Heng Zhang3,4,
  5. Colby Shad Thaxton3,4,
  6. Jaime Chowaniec1,
  7. Emily A Waters5,
  8. Thomas J Meade5,
  9. Douglas E Vaughan2,
  10. Harris Perlman1
  1. 1Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  2. 2Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  3. 3Institute for BioNanotechnology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  4. 4Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  5. 5Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA
  1. Correspondence to Harris Perlman, Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Rheumatology, 240 East Huron Street, McGaw M338, Chicago, IL 60611, USA; h-perlman{at}northwestern.edu

Abstract

Objectives Patients with rheumatoid arthritis (RA) have a reduced life expectancy due to increased cardiovascular disease. The lack of a suitable animal model resembling both RA and atherosclerosis has hindered studies demonstrating a direct link between systemic inflammation in RA and the development of atherosclerosis. Our objective was to overcome this barrier by generating an animal model (K/BxAg7) that spontaneously develops both RA-like disease and atherosclerosis.

Methods Arthritis severity was evaluated using clinical indices and immunohistochemical staining of ankle joint specimens. Aortic atherosclerosis was delineated via Sudan IV staining and immunohistochemical analysis. Serum cholesterol and lipoprotein levels were measured using enzymatic assays. Serum levels of cytokines, chemokines and adipokines were determined by Luminex assays.

Results K/BxAg7 mice developed a destructive arthropathy followed by prominent aortic atherosclerosis. These animals also displayed dyslipidaemia, characterised by reduced serum levels of total cholesterol and high-density lipoprotein, and increased low-density lipoprotein (LDL)/vLDL compared with control mice. Further, there were higher levels of circulating inflammatory mediators, such as interleukin-6, sRANKL and CCL5 in atherosclerotic K/BxAg7 mice compared with controls. Treatment with etanercept reduced arthritis and atherosclerosis development in K/BxAg7 mice.

Conclusions K/BxAg7 mice recapitulate the same sequence of events occurring in patients with RA, namely an erosive, inflammatory arthritis followed by atherosclerosis. These data suggest that the K/BxAg7 mouse is a novel system for investigating the interplay between systemic inflammation occurring in RA and the development of atherosclerosis.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

https://doi.org/10.1136/annrheumdis-2012-201431

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    Footnotes

    • Funding NIH.

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement We will share all data and resources that relate to this manuscript.