0002405: Inhibition of Collagenolysis in Canine Cranial Cruciate Ligament During Rupture

Grant Amount: $89,283

Peter Muir, BVSc, PhD; University of Wisconsin, Madison

April 1, 2003 - March 31, 2005

Sponsor(s): Great Pyrenees Club of America, Mastiff Club of America, National Amateur Retriever Club, Newfoundland Club of America Charitable Trust, Orthopedic Foundation for Animals, Poodle Club of America Foundation

Breed(s): -All Dogs

Research Program Area: Musculoskeletal Conditions and Disease

Abstract

The long-range goal of this work is to study tissue repair in the canine cruciate ligament and to determine what causes cruciate rupture. Our objective is to determine whether the presence of two enzymes, tartrate-resistant acid phosphatase and cathepsin K, causes excessive breakdown of collagen within the cruciate ligament, and weakening of the ligament. It is currently believed that excessive expression of this type of enzyme is an important factor causing cruciate rupture. Having determined whether these enzymes cause breakdown of collagen within the cruciate ligament, this knowledge will offer new insight into cruciate rupture in dogs and facilitate development of new treatments. To accomplish the objective of this application, we will determine whether these enzymes are released into the knee joint fluid in dogs with cruciate rupture. Using a tissue culture technique with pieces of ruptured ligament collected from surgical patients, we will also determine whether treatment of the ligament with enzyme inhibitors prevents excessive breakdown of ligament collagen. Upon completion of this work, we expect to have gained a detailed understanding of the role of these ligament-dissolving enzymes in cruciate rupture. We also expect that the results will lead to development of new medical treatments for cruciate rupture.

Publication(s)

Barrett, J. G., Hao, Z., Graf, B. K., Kaplan, L. D., Heiner, J. P., & Muir, P. (2005). Inflammatory changes in ruptured canine cranial and human anterior cruciate ligaments. American Journal of Veterinary Research, 66(12), 2073–2080. https://doi.org/10.2460/ajvr.2005.66.2073

Bleedorn, J. A., Greuel, E. N., Manley, P. A., Schaefer, S. L., Markel, M. D., Holzman, G., & Muir, P. (2011). Synovitis in Dogs with Stable Stifle Joints and Incipient Cranial Cruciate Ligament Rupture: A Cross-Sectional Study. Veterinary Surgery, 40(5), 531–543. https://doi.org/10.1111/j.1532-950X.2011.00841.x

Muir, P., Danova, N. A., Argyle, D. J., Manley, P. A., & Hao, Z. (2005). Collagenolytic Protease Expression in Cranial Cruciate Ligament and Stifle Synovial Fluid in Dogs with Cranial Cruciate Ligament Rupture. Veterinary Surgery, 34(5), 482–490. https://doi.org/10.1111/j.1532-950X.2005.00073.x

Muir, P., Manley, P. A., & Hao, Z. (2006). Collagen fragmentation in ruptured canine cranial cruciate ligament explants. The Veterinary Journal, 172(1), 121–128. https://doi.org/10.1016/j.tvjl.2005.03.012

Muir, P., Manley, P. A., & Hao, Z. (2007). COL-3 inhibition of collagen fragmentation in ruptured cranial cruciate ligament explants from dogs with stifle arthritis. The Veterinary Journal, 174(2), 403–406. https://doi.org/10.1016/j.tvjl.2006.07.007

Muir, P., Schamberger, G. M., Manley, P. A., & Hao, Z. (2005). Localization of Cathepsin K and Tartrate-Resistant Acid Phosphatase in Synovium and Cranial Cruciate Ligament in Dogs with Cruciate Disease. Veterinary Surgery, 34(3), 239–246. https://doi.org/10.1111/j.1532-950X.2005.00036.x

Muir, P., Schwartz, Z., Malek, S., Kreines, A., Cabrera, S. Y., Buote, N. J., … Hao, Z. (2011). Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture. PLoS ONE, 6(10), e25331. https://doi.org/10.1371/journal.pone.0025331