(Verbatim from the Applicant): A disruption in the healthy balance between the biomechanical environment and the cartilage structure is thought to initiate the pathogenesis of osteoarthritis (OA). Apoptosis may be an early consequence of this disruption. A long-term objective is to identify and understand the cartilage changes which occur at the initiation of pathogenesis. This understanding is prerequisite for early intervention and prevention of a disease that costs society much in terms of human suffering and economic loss. The in vivo model, in which canine hip dysplasia is invariably accompanied by OA, gives the unique opportunity to look very early at changes in a spontaneous (non-surgical) model of OA. The in vitro model, which uses impact damage to mimic select early aspects of the disease process, will aid in dissection of the mechanisms of pathogenesis. Grounded in a solid body of information about these models, observations reported in the literature, and exciting preliminary data, the hypothesis is that a level of impact loading of articular cartilage sufficient to cause both matrix damage and cell death at the site of injury releases intercellular signals which propagate a wave of apoptosis radially and transversely through the cartilage. If this apoptosis cannot be prevented by normal and appropriate checks and balances within the cartilage, it will contribute to the cartilage degeneration characteristic of the early pathogenesis of OA.
The Specific Aims address the questions: (1) why does cell death spread within impact-loaded cartilage beyond the site of original damage?; (2a) how important is cell death in triggering the matrix degeneration and other changes characteristic of the pathogenesis of OA?; and (2b) conversely, will a cartilage environment capable of preventing or delaying a cell's decision to die be more resistant to development of osteoarthritic changes? To answer these questions, we will inflict impact damage in the cores of explanted cartilage. The role of the signaling factors involved, as well as the nature of the secondary wave of cell death, whether apoptosis, necrosis, or both will be defined. The coincidence of cell death and the appearance of other markers of OA will be determined and an attempt made to inhibit matrix damage by inhibiting apoptosis. We will select dogs at high and low risk of developing OA. Cell death at the area of lesion predilection will be examined and potential inhibitors of cell death, as well as death signals will be looked for. The expectation is that by interdigitating information about cell death and cartilage degeneration from these unique in vivo and in vitro models, important new information about the earliest stages in the pathogenesis of OA will emerge.
