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. 2005 Jan 7;64(7):981–987. doi: 10.1136/ard.2004.029710

A longitudinal study on an autoimmune murine model of ankylosing spondylitis

T Bardos 1, Z Szabo 1, M Czipri 1, C Vermes 1, M Tunyogi-Csapo 1, R Urban 1, K Mikecz 1, T Glant 1
PMCID: PMC1755557  PMID: 15640265

Abstract

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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Figure 1.

Figure 1

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 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 with human cartilage PG in the first experimental group, and five killed weekly.

Figure 2.

Figure 2

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 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 articular surfaces indicated with dotted lines in (B), as early as 4–6 weeks after the onset of arthritis in the peripheral joints. This was followed shortly by massive proliferation of chondrocyte-like cells (white arrowheads in (C), which formed a junction of chondrophytes, resulting in complete ankylosis of the sacroiliac joint (D). The tissue sections were stained with haematoxylin and eosin.

Figure 3.

Figure 3

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 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). Massive enthesitis develops with a pannus-like tissue eroding the rest of the IVD at the ventral side of the spine. Safranin O/fast green staining (B, E) demonstrates the PG content (red) in the growth plate (GP), in the cartilaginous end plate (EP), and, less intensively, in the annulus fibrosus (AF) and nucleus pulposus (NP) of the normal (B) or spondylitic (E) spine. In the affected spine (E) the annulus fibrosus and the nucleus pulposus have been completely resorbed and the end plate (black arrowheads) is essentially absent (E). The neighbouring vertebral bodies are connected by chondrophytes (black arrows), which ankylose the spine. Polarisation microscopy of sections stained with picrosirius red (panels C and F) indicates that the regularity of collagen fibres, due to parallel orientation in the normal annulus fibrosus (C; white arrows), is completely lost in the annulus fibrosus of the disk affected by inflammation (F).

Figure 4.

Figure 4

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 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 bodies (A; control), which became moderately deformed by 12 weeks (B) and grossly altered by 24 weeks (C) after the onset of peripheral joint inflammation. White arrows show chondrophyte formation at the marginal regions of the vertebral bodies.

Figure 5.

Figure 5

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 (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 four times with PG and killed on week 30 of the experiment—that is, 21 weeks after the last immunisation. (B) Significant differences when male mice and female mice with arthritis or spondylitis, or both, were compared: *p<0.05; **p<0.01.

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