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Ann Rheum Dis. Jul 2005; 64(7): 981–987.
Published online Jan 7, 2005. doi:  10.1136/ard.2004.029710
PMCID: PMC1755557

A longitudinal study on an autoimmune murine model of ankylosing spondylitis


Background: Proteoglycan aggrecan (PG)-induced arthritis (PGIA) is the only systemic autoimmune murine model which affects the axial skeleton, but no studies have been performed characterising the progression of spine involvement.

Objectives: To follow pathological events in experimental spondylitis, and underline its clinical, radiographic, and histological similarities to human ankylosing spondylitis (AS); and to determine whether the spondyloarthropathy is a shared phenomenon with PGIA, or an "independent" disease.

Methods: Arthritis/spondylitis susceptible BALB/c and resistant DBA/2 mice, and their F1 and F2 hybrids were immunised with cartilage PG, and radiographic and histological studies were performed before onset and weekly during the progression of spondylitis.

Results: About 70% of the PG immunised BALB/c mice develop spondyloarthropathy (proteoglycan-induced spondylitis (PGISp), and the progression of the disease is very similar to human AS. It begins with inflammation in the sacroiliac joints and with enthesitis, and then progresses upwards, affecting multiple intervertebral disks. In F2 hybrids of arthritis/spondylitis susceptible BALB/c and resistant DBA/2 mice the incidence of arthritis was 43.5%, whereas the incidence of spondylitis was >60%. Some arthritic F2 hybrid mice had no spondylitis, whereas others developed spondylitis in the absence of peripheral arthritis.

Conclusions: The PGISp model provides a valuable tool for studying autoimmune reactions in spondylitis, and identifying genetic loci associated with spondyloarthropathy.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med. 1973 Apr 5;288(14):704–706. [PubMed]
  • Robinson WP, van der Linden SM, Khan MA, Rentsch HU, Cats A, Russell A, Thomson G. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum. 1989 Sep;32(9):1135–1141. [PubMed]
  • Said-Nahal R, Miceli-Richard C, Berthelot JM, Duché A, Dernis-Labous E, Le Blévec G, Saraux A, Perdriger A, Guis S, Claudepierre P, et al. The familial form of spondylarthropathy: a clinical study of 115 multiplex families. Groupe Français d'Etude Génétique des Spondylarthropathies. Arthritis Rheum. 2000 Jun;43(6):1356–1365. [PubMed]
  • Brown MA, Pile KD, Kennedy LG, Campbell D, Andrew L, March R, Shatford JL, Weeks DE, Calin A, Wordsworth BP. A genome-wide screen for susceptibility loci in ankylosing spondylitis. Arthritis Rheum. 1998 Apr;41(4):588–595. [PubMed]
  • Laval SH, Timms A, Edwards S, Bradbury L, Brophy S, Milicic A, Rubin L, Siminovitch KA, Weeks DE, Calin A, et al. Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci. Am J Hum Genet. 2001 Apr;68(4):918–926. [PMC free article] [PubMed]
  • Ebringer RW, Cawdell DR, Cowling P, Ebringer A. Sequential studies in ankylosing spondylitis. Association of Klebsiella pneumoniae with active disease. Ann Rheum Dis. 1978 Apr;37(2):146–151. [PMC free article] [PubMed]
  • Hermann E, Sucké B, Droste U, Meyer zum Büschenfelde KH. Klebsiella pneumoniae-reactive T cells in blood and synovial fluid of patients with ankylosing spondylitis. Comparison with HLA-B27+ healthy control subjects in a limiting dilution study and determination of the specificity of synovial fluid T cell clones. Arthritis Rheum. 1995 Sep;38(9):1277–1282. [PubMed]
  • Cancino-Díaz M, Curiel-Quesada E, García-Latorre E, Jiménez-Zamudio L. Cloning and sequencing of the gene that codes for the Klebsiella pneumoniae GroEL-like protein associated with ankylosing spondylitis. Microb Pathog. 1998 Jul;25(1):23–32. [PubMed]
  • Ebringer A, Wilson C. HLA molecules, bacteria and autoimmunity. J Med Microbiol. 2000 Apr;49(4):305–311. [PubMed]
  • Nickerson CL, Hogen KL, Luthra HS, David CS. Effect of H-2 genes on expression of HLA-B27 and Yersinia-induced arthritis. Scand J Rheumatol Suppl. 1990;87:85–90. [PubMed]
  • Ugrinovic S, Mertz A, Wu P, Braun J, Sieper J. A single nonamer from the Yersinia 60-kDa heat shock protein is the target of HLA-B27-restricted CTL response in Yersinia-induced reactive arthritis. J Immunol. 1997 Dec 1;159(11):5715–5723. [PubMed]
  • Yu David, Kuipers Jens G. Role of bacteria and HLA-B27 in the pathogenesis of reactive arthritis. Rheum Dis Clin North Am. 2003 Feb;29(1):21–vi. [PubMed]
  • Schwimmbeck PL, Yu DT, Oldstone MB. Autoantibodies to HLA B27 in the sera of HLA B27 patients with ankylosing spondylitis and Reiter's syndrome. Molecular mimicry with Klebsiella pneumoniae as potential mechanism of autoimmune disease. J Exp Med. 1987 Jul 1;166(1):173–181. [PMC free article] [PubMed]
  • Gonzalez-Roces S, Alvarez MV, Gonzalez S, Dieye A, Makni H, Woodfield DG, Housan L, Konenkov V, Abbadi MC, Grunnet N, et al. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. Tissue Antigens. 1997 Feb;49(2):116–123. [PubMed]
  • Glant T, Csongor J, Szücs T. Immunopathologic role of proteoglycan antigens in rheumatoid joint disease. Scand J Immunol. 1980;11(3):247–252. [PubMed]
  • Golds EE, Stephen IB, Esdaile JM, Strawczynski H, Poole AR. Lymphocyte transformation to connective tissue antigens in adult and juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, and a nonarthritic control population. Cell Immunol. 1983 Nov;82(1):196–209. [PubMed]
  • Mikecz K, Glant TT, Baron M, Poole AR. Isolation of proteoglycan-specific T lymphocytes from patients with ankylosing spondylitis. Cell Immunol. 1988 Mar;112(1):55–63. [PubMed]
  • Jobanputra P, Choy EH, Kingsley GH, Sieper J, Palacios-Boix AA, Heinegård D, Panayi GS. Cellular immunity to cartilage proteoglycans: relevance to the pathogenesis of ankylosing spondylitis. Ann Rheum Dis. 1992 Aug;51(8):959–962. [PMC free article] [PubMed]
  • Zou J, Zhang Y, Thiel A, Rudwaleit M, Shi S-L, Radbruch A, Poole R, Braun J, Sieper J. Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylosing spondylitis and rheumatoid arthritis. Rheumatology (Oxford) 2003 Jul;42(7):846–855. [PubMed]
  • Lipson SJ, Muir H. Vertebral osteophyte formation in experimental disc degeneration. Morphologic and proteoglycan changes over time. Arthritis Rheum. 1980 Mar;23(3):319–324. [PubMed]
  • Mahowald ML, Krug H, Taurog J. Progressive ankylosis in mice. An animal model of spondylarthropathy. I. Clinical and radiographic findings. Arthritis Rheum. 1988 Nov;31(11):1390–1399. [PubMed]
  • Moskowitz RW, Ziv I, Denko CW, Boja B, Jones PK, Adler JH. Spondylosis in sand rats: a model of intervertebral disc degeneration and hyperostosis. J Orthop Res. 1990 May;8(3):401–411. [PubMed]
  • Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell. 1990 Nov 30;63(5):1099–1112. [PubMed]
  • Miyamoto S, Yonenobu K, Ono K. Experimental cervical spondylosis in the mouse. Spine (Phila Pa 1976) 1991 Oct;16(10 Suppl):S495–S500. [PubMed]
  • Khare SD, Luthra HS, David CS. Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies. J Exp Med. 1995 Oct 1;182(4):1153–1158. [PMC free article] [PubMed]
  • Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank gene in control of tissue calcification and arthritis. Science. 2000 Jul 14;289(5477):265–270. [PubMed]
  • Harmey Dympna, Hessle Lovisa, Narisawa Sonoko, Johnson Kristen A, Terkeltaub Robert, Millán José Luis. Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. Am J Pathol. 2004 Apr;164(4):1199–1209. [PMC free article] [PubMed]
  • Glant TT, Mikecz K, Arzoumanian A, Poole AR. Proteoglycan-induced arthritis in BALB/c mice. Clinical features and histopathology. Arthritis Rheum. 1987 Feb;30(2):201–212. [PubMed]
  • Glant TT, Bárdos T, Vermes C, Chandrasekaran R, Valdéz JC, Otto JM, Gerard D, Velins S, Lovász G, Zhang J, et al. Variations in susceptibility to proteoglycan-induced arthritis and spondylitis among C3H substrains of mice: evidence of genetically acquired resistance to autoimmune disease. Arthritis Rheum. 2001 Mar;44(3):682–692. [PubMed]
  • Glant Tibor T, Finnegan Alison, Mikecz Katalin. Proteoglycan-induced arthritis: immune regulation, cellular mechanisms, and genetics. Crit Rev Immunol. 2003;23(3):199–250. [PubMed]
  • Shi Shuiliang, Ciurli Cristina, Cartman Annie, Pidoux Isabelle, Poole A Robin, Zhang Yiping. Experimental immunity to the G1 domain of the proteoglycan versican induces spondylitis and sacroiliitis, of a kind seen in human spondylarthropathies. Arthritis Rheum. 2003 Oct;48(10):2903–2915. [PubMed]
  • Zhang Yiping. Animal models of inflammatory spinal and sacroiliac joint diseases. Rheum Dis Clin North Am. 2003 Aug;29(3):631–645. [PubMed]
  • Mikecz K, Glant TT, Poole AR. Immunity to cartilage proteoglycans in BALB/c mice with progressive polyarthritis and ankylosing spondylitis induced by injection of human cartilage proteoglycan. Arthritis Rheum. 1987 Mar;30(3):306–318. [PubMed]
  • Glant TT, Cs-Szabó G, Nagase H, Jacobs JJ, Mikecz K. Progressive polyarthritis induced in BALB/c mice by aggrecan from normal and osteoarthritic human cartilage. Arthritis Rheum. 1998 Jun;41(6):1007–1018. [PubMed]
  • Glant Tibor T, Mikecz Katalin. Proteoglycan aggrecan-induced arthritis: a murine autoimmune model of rheumatoid arthritis. Methods Mol Med. 2004;102:313–338. [PubMed]
  • Otto JM, Cs-Szabó G, Gallagher J, Velins S, Mikecz K, Buzás EI, Enders JT, Li Y, Olsen BR, Glant TT. Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis. Arthritis Rheum. 1999 Dec;42(12):2524–2531. [PubMed]
  • Bárdos T, Kamath RV, Mikecz K, Glant TT. Anti-inflammatory and chondroprotective effect of TSG-6 (tumor necrosis factor-alpha-stimulated gene-6) in murine models of experimental arthritis. Am J Pathol. 2001 Nov;159(5):1711–1721. [PMC free article] [PubMed]
  • Czipri Mátyás, Otto Jeffrey M, Cs-Szabó Gabriella, Kamath Rajesh V, Vermes Csaba, Firneisz Gábor, Kolman Kevin J, Watanabe Hideto, Li Yefu, Roughley Peter J, et al. Genetic rescue of chondrodysplasia and the perinatal lethal effect of cartilage link protein deficiency. J Biol Chem. 2003 Oct 3;278(40):39214–39223. [PubMed]
  • Kimmel CA, Trammell C. A rapid procedure for routine double staining of cartilage and bone in fetal and adult animals. Stain Technol. 1981 Sep;56(5):271–273. [PubMed]
  • Bárdos Tamás, Mikecz Katalin, Finnegan Alison, Zhang Jian, Glant Tibor T. T and B cell recovery in arthritis adoptively transferred to SCID mice: antigen-specific activation is required for restoration of autopathogenic CD4+ Th1 cells in a syngeneic system. J Immunol. 2002 Jun 15;168(12):6013–6021. [PubMed]
  • Schmidt MB, Mow VC, Chun LE, Eyre DR. Effects of proteoglycan extraction on the tensile behavior of articular cartilage. J Orthop Res. 1990 May;8(3):353–363. [PubMed]
  • Waggett AD, Ralphs JR, Kwan AP, Woodnutt D, Benjamin M. Characterization of collagens and proteoglycans at the insertion of the human Achilles tendon. Matrix Biol. 1998 Mar;16(8):457–470. [PubMed]
  • Pearce RH, Grimmer BJ, Adams ME. Degeneration and the chemical composition of the human lumbar intervertebral disc. J Orthop Res. 1987;5(2):198–205. [PubMed]
  • Kang JD, Stefanovic-Racic M, McIntyre LA, Georgescu HI, Evans CH. Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine (Phila Pa 1976) 1997 May 15;22(10):1065–1073. [PubMed]
  • Szántó Sándor, Bárdos Tamás, Szabó Zoltán, David Chella S, Buzás Edit I, Mikecz Katalin, Glant Tibor T. Induction of arthritis in HLA-DR4-humanized and HLA-DQ8-humanized mice by human cartilage proteoglycan aggrecan but only in the presence of an appropriate (non-MHC) genetic background. Arthritis Rheum. 2004 Jun;50(6):1984–1995. [PubMed]
  • Doege KJ, Sasaki M, Kimura T, Yamada Y. Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms. J Biol Chem. 1991 Jan 15;266(2):894–902. [PubMed]
  • Walcz E, Deák F, Erhardt P, Coulter SN, Fülöp C, Horvath P, Doege KJ, Glant TT. Complete coding sequence, deduced primary structure, chromosomal localization, and structural analysis of murine aggrecan. Genomics. 1994 Jul 15;22(2):364–371. [PubMed]
  • Kabasakal Y, Garrett SL, Calin A. The epidemiology of spondylodiscitis in ankylosing spondylitis--a controlled study. Br J Rheumatol. 1996 Jul;35(7):660–663. [PubMed]
  • Braun J, Bollow M, Sieper J. Radiologic diagnosis and pathology of the spondyloarthropathies. Rheum Dis Clin North Am. 1998 Nov;24(4):697–735. [PubMed]
  • Fry TR, Eurell JC, Johnson AL, Brown MD, Losonsky JM, Schaeffer DJ. Radiographic and histologic effects of chondroitinase ABC on normal canine lumbar intervertebral disc. Spine (Phila Pa 1976) 1991 Jul;16(7):816–819. [PubMed]
  • Taurog JD, Maika SD, Satumtira N, Dorris ML, McLean IL, Yanagisawa H, Sayad A, Stagg AJ, Fox GM, Lê O'Brien A, et al. Inflammatory disease in HLA-B27 transgenic rats. Immunol Rev. 1999 Jun;169:209–223. [PubMed]
  • Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994 Dec 1;180(6):2359–2364. [PMC free article] [PubMed]
  • Brown Matthew A, Brophy Sinead, Bradbury Linda, Hamersma Jasmin, Timms Andrew, Laval Steven, Cardon Lon, Calin Andrei, Wordsworth B Paul. Identification of major loci controlling clinical manifestations of ankylosing spondylitis. Arthritis Rheum. 2003 Aug;48(8):2234–2239. [PubMed]
  • Karopoulos C, Rowley MJ, Ilic MZ, Handley CJ. Presence of antibodies to native G1 domain of aggrecan core protein in synovial fluids from patients with various joint diseases. Arthritis Rheum. 1996 Dec;39(12):1990–1997. [PubMed]
  • Guerassimov A, Zhang Y, Banerjee S, Cartman A, Leroux JY, Rosenberg LC, Esdaile J, Fitzcharles MA, Poole AR. Cellular immunity to the G1 domain of cartilage proteoglycan aggrecan is enhanced in patients with rheumatoid arthritis but only after removal of keratan sulfate. Arthritis Rheum. 1998 Jun;41(6):1019–1025. [PubMed]
  • Li NL, Zhang DQ, Zhou KY, Cartman A, Leroux JY, Poole AR, Zhang YP. Isolation and characteristics of autoreactive T cells specific to aggrecan G1 domain from rheumatoid arthritis patients. Cell Res. 2000 Mar;10(1):39–49. [PubMed]

Figures and Tables

Figure 1
 Time course of immunisation, number of animals killed and analysed weekly, and the time of onset of arthritis in peripheral joints (PGIA; thick black arrow) and spondylitis (PGISp; thick white arrow). A total of 210 female BALB/c mice were immunised ...
Figure 2
 Inflammation of the sacroiliac joints and progression of ankylosis in PG immunised BALB/c mice with spondylitis. The normal sacroiliac joint (A), which is first eroded by a synovial pannus-like hyperproliferative tissue (black arrows) at the ...
Figure 3
 Cervical spine segments in (A, B, C) normal mice and in (D, E, F) mice afflicted with spondylitis. The affected disks are shown with the ankylosing osteophytes (black arrows: IVD C4/C5), which protrude and compress the spinal cord (SpC) (D). ...
Figure 4
 Progression of spondylitis in the lumbar spine (L3-5) in PG immunised BALB/c mice. Alizarin red stains bone red, while alcian blue stains the cartilaginous structures blue. Black arrowheads indicate the cartilaginous growth plates of the vertebral ...
Figure 5
 (A) Analysis and comparison of PG-induced arthritis (PGIA: A) and PG-induced spondylitis (PGISp: Sp) in 81 BALB/c (B/c), 48 DBA/2 (D/2) mice and their F1 and F2 hybrids (BALB/c x DBA/2) immunised with human cartilage PG. All mice were injected ...

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