Osteoarthritis

Overview:

Animal models of osteoarthritis (OA) that are commonly used to study the pathogenesis of cartilage degeneration and potential therapy can be either naturally occurring or induced. Induction involves surgical manipulation or injection of matrix modifying agents into the joint. The knee joint is the most common joint that is affected (spontaneous OA) or utilized (induced). Spontaneous OA occurs reliably only in certain animal species, but some form of surgical or chemical OA can be induced in any animal species. By using different animals, one can achieve diversity in the lesion characteristics. Alternatively, diverse lesions of varying severity can be obtained by applying different injuries to animals of the same species. This would then permit investigation of different types of therapeutic interventions. Recent studies that have compared profiles of cartilage degradation in various models with those in human or spontaneous animal disease indicate that most OA models have more similarities than differences (2, 3, 4, 5). Model selection for a particular purpose generally comes down to selection of the desired animal species and, within that species, having the desired morphologic and biochemical changes that will allow appropriate evaluation of the efficacy of a potential therapeutic agent in a reasonable period of time.

The diversity of models and species often leaves the investigator confused about the choice of an appropriate model, yet, as a result of preliminary work, the investigator may already have chosen a particular animal species. A further important consideration relates to the morphologic features of the lesion and to knowledge about mediators involved in the pathogenesis, particularly when a pharmaceutic agent is being tested. For example, inhibitors of collagenase should be tested in models where collagen degradation is of sufficient severity to generate an observable morphologic change. Aggrecanase inhibitors, on the other hand, should be tested in models where the primary morphologic change is proteoglycan loss, so that collagen loss does not obscure the proteoglycan evaluation. Another way to address this issue within most instability models is by individual evaluation of load-bearing zones of articular cartilage. In virtually all surgical models, there are areas of mechanical abrasion adjacent to areas of milder, enzymatic degradation. Histopathologic evaluation that takes into account these zonal variabilities will often be as useful as utilizing multiple models of different severity. However, just as criteria for efficacy are set at the onset of a human clinical trial, animal studies must also have pre-defined parameters. Criteria for success should depend on the potential limits of the agent under investigation.

References:

  1. Bendele A.M. Animal Models. In Bone and Osteoarthritis (Topics in Bone Biology, Volume 4). Editors Felix Bronner and Mary C. Farach-Carson, Springer-Verlag London. 2007
  2. Bendele AM, Animal models of osteoarthritis. J Musculoskel Neuron Interact 2001;1(4):363-376.
  3. Janusz MJ, Little CB, King LE, Hookfin EB, Brown KK, Heitmeyer SA, Caterson B, Poole AR, Taiwo YO. Detection of aggrecanase-and MMP-generated catabolic neoepitopes in the rat iodoacetate model of cartilage degeneration. Ostoarthritis Cartilage. 2004;12:720-728.
  4. Price JS, Chambers MG, Poole AR, Fradin A, Mason RM. Comparison of collagenase-cleaved articular cartilage collagen in mice in the naturally occurring STR/ort model of osteoarthritis and in collagen-induced arthritis. Osteoarthritis Cartilage. 2002;10:172-179.
  5. Van den Berg. Lessons from animal models of osteoarthritis. Current Opinion Rheumatology. 2001;13:452-456.

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