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Rabbit Model of Osteoarthritis

We have established and validated a rabbit anterior cruciate ligament (ACL) transection model or osteoarthritis(OA) and shown extensively its utility for investigating the pathogenesis of OA, for evaluating drug efficacy1, and for validation of novel joint imaging technology2,3,4.

This relatively short term model (8 weeks) rapidly and reproducibly leads to articular cartilage degeneration characterized by fibrillation, focal erosions, and eburnation of bone (refer to figure 1). Periarticular osteophytes also develop. These changes are similar to those observed in human OA. This model is ideal in drug candidate selection and testing because it can be analyzed not only by imaging and histology, but also by molecular analyses of cartilage degeneration and the use of biomarkers to assess this degradation. Moreover, orally delivered drugs can be administered effectively and efficiently in the animal's feed1.

 

Evaluations

In OA, cartilage metabolism is altered, resulting in increased synthesis and degradation of matrix molecules leading to degeneration.

1. Gross morphology

  • Cartilage:
    The femoral condyles and tibial plateau are photographed using a digital camera with and without application of India ink to contrast cartilage lesions. Gross morphological changes of the femoral condyles and tibial plateaus will be graded.

  • Osteophytes:
    The presence or absence of osteophytes is determined for each compartment, such as the medial femoral condyle, lateral femoral condyle, medial tibial plateau, and lateral tibial plateau.

2. Histology/immunohistochemistry

  • Safranin-O/fast green-stained sections of specific sites in each compartment are evaluated for cartilage degeneration according to a modified Mankin's grading system.

 

Figure 1

Panel A: no lesions on femoral condyle from a normal rabbit.
Panel B: closed arrow shows areas of fibrillation. Open arrows show erosion of the articular cartilage to the subchondral bone.
Panel C: histological section of a normal femoral condyle stained with Safranin-O.
Panel D: histological section from femoral condyle of an experimental rabbit showing a large ulceration of articular cartilage extending to the subchondral bone.

  • Immunohistochemical staining (available shortly), of articular cartilage for collagen type II cleavage by collagenase5,6 collagen II denaturation7,8 collagen type II synthesis9 and aggrecan turnover [CS-846 epitope]10.

3. Biomarker Assays

We use biomarkers provided by IBEX Technologies Inc.. Our assays quantify the degradation and synthesis/turnover of cartilage molecules in synovial fluid and serum. Our evaluations include assays for:

  • Type II collagen cleavage by collagenase 11,12 (C2C assay)

  • Type II collagen propeptide synthesis9,10,13 (CP II assay)

  • Aggrecan turnover13,15 [CS-846 assay]

These combined analyses of the cartilage permit the evaluation of the chondroprotective effects of experimental therapies in this model.

For more information, contact:

Johnathan Riley
Managing Director
Phone: 416-586-3167

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Reference List

1. Tiraloche, G., Girard, C., Chouinard, L., Sampalis, J., Moquin, L., Ionescu, M., Poole, A.R., Laverty, S. Effect of Oral Glucosamine on cartilage degradation in a rabbit model of osteoarthritis. Arthritis and Rheumatism, 2005; 52: 1118-1128.

2. Spriet, M., Girard, C., Foster. S., Kirkley. S., Holdsworth, D., Laverty, S. The validation of a 40 MHz B-scan ultrasound biomicroscope for the evaluation of osteoarthritis lesions in an animal model. Osteoarthritis and Cartilage. 2005; 13: 171-179

3. Batiste, D.L., Kirkley, A., Laverty, S., Thain, L.M., Spouge, A.R., Holdsworth, D.W. Ex vivo characterization of articular cartilage and bone lesions in a rabbit ACL transection model of osteoarthritis using MRI and micro-CT. Osteoarthritis Cartilage. 2004; 12: 986-996

4. Batiste, D.L., Kirkley, A., Laverty, S. Thain, L., Spouge, A.R., Gati, P.J., Foster, D.W. High-resolution MRI and micro-CT in an ex vivo rabbit anterior cruciate ligament transection model of osteoarthritis. Osteoarthritis Cartilage. 2004; 12: 614-626.

5. Billinghurst, R.C., Dahlberg, L., Ionescu, M., Reiner, A., Bourne, R., Rorabeck, C., Mitchell, P., Hambor, J., Diekmann, O., Tschesche, H., Chen, J., Van Wart, H., Poole, A.R. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. Journal of Clinical Investigation. 1997; 99: 1534-1545.

6. Stoop, R., van der Kraan, P.M., Buma, P., Hollander, A.P., Billinghurst, R.C., Poole, A.R., van den Berg, W.B. Type II collagen degradation in spontaneous osteoarthritis in C57Bl/6 and BALB/c mice. Arthritis and Rheumatism. 1999; 42: 2381-2389.

7. Hollander, A.P., Pidoux, I., Reiner, A., Rorabeck, C., Bourne, R. Poole, A.R. Damage to type II collagen in ageing and osteoarthritis: starts at the articular surface, originates around chondrocytes and extends into the cartilage with progressive degeneration. Journal of Clinical Investigation. 1995; 96: 2859-2869.

8. Hollander, A.P., Heathfield, T.F., Webber, C., Iwata, Y., Rorabeck, C., Bourne, R. Poole, A.R. Increased damage to type II collagen in osteoarthritic cartilage detected by a new immunoassay. Journal of Clinical Investigation. 1994; 93: 1722-1732.

9. Nelson, F., Dahlberg, L., Laverty, S., Reiner, A., Pidoux, I., Ionescu, M., Fraser, G., Brooks, E., Tanzer, M., Rosenberg, L.C., Dieppe, P., Poole, A.R.. Evidence for altered synthesis of type II collagen in patients with osteoarthritis. Journal of Clinical Investigation. 1998; 102: 2115-2125.

10. Rizkalla, G., Reiner, A., Bogoch, E. Poole, A.R.. Studies of the articular cartilage proteoglycan aggrecan in health and osteoarthritis: evidence for molecular heterogeneity and extensive molecular changes in disease. Journal of Clinical Investigation. 1992; 90: 2268-2277.

11. Kojima, T., Mwale, F., Yasuda, T., Girard, C., Poole, A.R. Laverty, S. The comparative degradation of type IX and type II collagens and proteoglycan in articular cartilage in early experimental inflammatory arthritis. Arthritis Rheumatism. 2001; 44: 120-127.

12. Poole, A.R., Ionescu, M., Fitzcharles, M.A., Billinghurst, R.C. The assessment of cartilage degradation in vivo: Development of an immunoassay for the measurement in body fluids of type II collagen cleaved by collagenases. J. Immunological Methods. 2004; 294: 145-153.

13. Mansson, B., Carey, D., Alini. M., Ionescu, M., Rosenberg, L.C., Poole, A.R., Heinegard, D., Saxne, T. Cartilage and bone metabolism in rheumatoid arthritis. Differences between rapid and slow progression of disease identified by serum markers of cartilage metabolism. Journal of Clinical Investigation. 1995; 95: 1071-1077.

14. Lohmander, L.S., Ionescu, M., Jugessur, H., Poole, A.R. Changes in joint cartilage aggrecan after knee injury and in osteoarthritis. Arthritis and Rheumatism. 1999; 42: 534-544.

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