Cruciate ligament pathogenesis and its role in the initiation and progression of osteoarthritis

The pathogenesis of cruciate ligament disease and how it may be linked to the initiation and progression of osteoarthritis was investigated using in vitro and in vivo models. Normal and diseased tissues were initially evaluated to differentially identify genes that may be involved in this disease process. Structural, degradative and inflammatory genes were found to be expressed differentially in these tissues. Gene expression data corresponded well to protein expression when investigated. The role of mechanotransduction in ligament health was investigated. Strain amplitude and duration was found to affect these differentially expressed genes. The Pond-Nuki model was utilized to investigate and confirmed the role of these genes in vivo. A novel method of matrix metalloproteinase detection was compared to traditional techniques and found to be superior to techniques currently utilized in the literature. Further investigation of these genes and molecules in cruciate ligament pathogenesis is warranted. Chapter 1: Introduction Osteoarthritis (OA) secondary to anterior cruciate ligament (ACL) deficiency is a common orthopaedic problem in dogs and humans. The Pond-Nuki anterior cruciate ligament transection (ACL-X) model is commonly utilized for the study of OA. While abnormal biomechanics are known to play a role in development of OA, the effects of molecular and biochemical alterations in ligament itself in the initiation and progression of OA are poorly understood. Because the ligament is a tissue composed of multiple cell types with a diverse and dynamic extracellular matrix, it is plausible that diseased intraarticular ligament could play a pivotal role in the initiation and exacerbation of secondary OA. The cruciate ligaments of the knee can be found within the joint cavity and these paired ligaments contribute to the overall stability of the joint. These ligaments are named according to the location of their attachment in the tibia. In humans, the ligament attaching to the tibia in a more anterior position than its paired ligament is known as the anterior cruciate ligament (ACL) and the ligament attaching in a more posterior position is known as the posterior cruciate ligament (PCL). Similarly, in animals, the ligament attaching to the tibia more cranially is known as the cranial cruciate ligament (CrCL) and the ligament attaching more caudally is known as the caudal cruciate ligament (CaCL). For all inclusive purposes the ACL in humans is analogous to the CrCL in animals. The two names for the same ligament arise from the directional terms needed to properly describe anatomy in bipeds as opposed to quadrupeds. Likewise, the PCL is analogous to the CaCL. The location, structure, and function are essentially the same so ACL/CrCL