Osteoarthritis is a crippling disease with serious consequences in terms of human suffering and economic loss. Cartilage changes occur early in the disease process, beginning with subtle perturbations to the matrix and the chondrocyte. They progress to more advanced stages where frank focal lesions, marked by fibrillation and loss of tissue integrity, are visible. At this time cartilage components including proteoglycans, collagens, and fibronectins are already affected. We were the first to report that fibronectin content is increased up to forty-fold over normal. The cartilage abnormalities eventually result in osteophyte formation and in denuding of underlying bone. To study the earliest changes, animal models are required. Canine hip osteoarthritis is an excellent model for study, not only of hip osteoarthritis, but also of the subtle early changes in the cartilage which precede the appearance of obvious cartilage lesions and which develop as a result of abnormal forces within the joint. It is a spontaneous model with a genetic component and requires no surgical intervention. Our objective is to understand the pathogenesis of cartilage degeneration during osteoarthritis to facilitate development of therapeutic interventions. We must dissect the sequence of events that progresses to cartilage degeneration by identifying the earliest biochemical metabolic, and structural changes and learning how they contribute to later morphological abnormalities.
Our Specific Aims are: 1) Identify cartilage changes, in vivo, in preosteoarthritic hip joints of dogs at high risk of developing osteoarthritis. We wish to determine if fibronectin accumulation and weakening of the collagen network are already evident at this early stage. A measure of hip laxity called the distraction index is a new, more precise measure which will permit selection of disease-prone dogs at an earlier age than heretofore possible. 2) Subject cartilage, in vitro, to mechanical loads which will damage the matrix, in order to mimic select initiating events that lead to degeneration. Culture of cartilage in a biochemically defined medium within the chambers of a cyclic loading machine developed in our laboratory will enable us to do this. 3) Identify the mechanism by which fibronectin accumulations contribute to matrix degeneration. Readily detectable high levels of fibronectin occur in early lesions, persist throughout the disease and are a well characterized feature of human and canine osteoarthritis. Our ability to manipulate the accumulation of fibronectin in explant culture will permit us to test the hypothesis that this increase has a critical role in the eventual weakening and degradation of cartilage. Studies of the in vivo and the in vitro models will interdigitate. Elevated fibronectin is just one component of the degenerating process in cartilage, but it is a prominent one. If we can delineate its relationship to the disease process from the earliest stages on, we gain insight into the mechanism of cartilage degeneration and its failure to repair during osteoarthritis.
|Chalmers, Heather J; Dykes, Nathan L; Lust, George et al. (2006) Assessment of bone mineral density of the femoral head in dogs with early osteoarthritis. Am J Vet Res 67:796-800|
|Todhunter, Rory J; Casella, George; Bliss, Stuart P et al. (2003) Power of a Labrador Retriever-Greyhound pedigree for linkage analysis of hip dysplasia and osteoarthritis. Am J Vet Res 64:418-24|
|Burton-Wurster, N; Liu, W; Matthews, G L et al. (2003) TGF beta 1 and biglycan, decorin, and fibromodulin metabolism in canine cartilage. Osteoarthritis Cartilage 11:167-76|
|Liu, Wenhua; Burton-Wurster, Nancy; Glant, Tibor T et al. (2003) Spontaneous and experimental osteoarthritis in dog: similarities and differences in proteoglycan levels. J Orthop Res 21:730-7|
|Todhunter, R J; Bliss, S P; Casella, G et al. (2003) Genetic structure of susceptibility traits for hip dysplasia and microsatellite informativeness of an outcrossed canine pedigree. J Hered 94:39-48|
|Todhunter, Rory J; Grohn, Yjo T; Bliss, Stuart P et al. (2003) Evaluation of multiple radiographic predictors of cartilage lesions in the hip joints of eight-month-old dogs. Am J Vet Res 64:1472-8|
|Chen, C T; Burton-Wurster, N; Borden, C et al. (2001) Chondrocyte necrosis and apoptosis in impact damaged articular cartilage. J Orthop Res 19:703-11|
|Levin, A; Burton-Wurster, N; Chen, C T et al. (2001) Intercellular signaling as a cause of cell death in cyclically impacted cartilage explants. Osteoarthritis Cartilage 9:702-11|
|Burton-Wurster, N; Gendelman, R; Chen, H et al. (1999) The cartilage-specific (V+C)- fibronectin isoform exists primarily in homodimeric and monomeric configurations. Biochem J 341 ( Pt 3):555-61|
|Farese, J P; Lust, G; Williams, A J et al. (1999) Comparison of measurements of dorsolateral subluxation of the femoral head and maximal passive laxity for evaluation of the coxofemoral joint in dogs. Am J Vet Res 60:1571-6|
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