Date of Award:

8-2020

Document Type:

Thesis

Degree Name:

Master of Science (MS)

Department:

Animal, Dairy, and Veterinary Sciences

Advisor/Chair:

Jeffrey B. Mason

Co-Advisor/Chair:

S. Clay Isom

Third Advisor:

Arnaud Van Wettere

Abstract

Humans rely on the health of their joints for stability and mobility in daily life. In a normal, healthy functioning joint, complex processes maintain joint tissues, including remodeling, lubrication, and immune function among many other tasks. Osteoarthritis (OA) is the most common joint disorder in the U.S. It becomes most prevalent in adults 60+ years of age and causes decreased mobility, discomfort, and in some cases, excruciating pain. In the biological processes of osteoarthritis, the metalloproteinase enzymes responsible for the degeneration of cartilage are upregulated. The inhibitors of metalloproteinase activity are known as Tissue Inhibitor of Metalloproteinases (TIMPs), which keep metalloproteinase activity in balance. However, an increased production of metalloproteinases has been noted in osteoarthritis-influenced cartilage. The current study focused on the up-regulation of TIMP-3 protein in vivo using the introduction of a TIMP-3 transgene. It was hypothesized that up-regulation of cell-produced, TIMP-3 protein would decrease proteoglycan degradation and slow OA progression in vivo. The use of sheep as a model has proven an effective technique for characterizing diseased joint issues and with our demonstrated method of inducing osteoarthritis over a period of months instead of years, we can make strides in advancing the understanding of the disease. Our methods involve two groups of surgically altered, mature, female sheep. One half underwent ovariectomy or removal of both ovaries (n = 7) and the other half, a Cranial Cruciate Ligament Desmotomy or transection of the cranial cruciate ligament, similar to the anterior cruciate ligament in humans (n = 8). OA was observed in sheep with these surgeries that were subjected to forced exercised at an oblique angle for four months. We found that the TIMP-3 treatment decreased gait stance time, average osteophytosis score and joint widening, but did not significantly affect joint space narrowing. The TIMP-3 transgene also decreased aggrecanase activity and serum glycosaminoglycan content and had a positive effect on urine glycosaminoglycan content. Through understanding and utilizing these new methods, we hope to refine our model to further research in this field and offer a better solution for those affected by OA.

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