Early osteoarthritic changes in a canine cranial cruciate deficient model

Abstract

Objective. To examine the early pathological, clinical, and biomarker responses that occur secondary to arthroscopic cranial cruciate ligament (CrCL) transection in the dog, for the purpose of determining the efficacy of a synthetic matrix metalloproteinase (MMP) inhibitor (BAY 12-9566) in slowing down the progression of osteoarthritis (OA). Methods. An arthroscopic technique was developed and used to successfully transect the right CrCL in 39 dogs. Twenty and 19 dogs were orally administered BAY 12-9566 or a placebo, respectively, starting at 2 weeks post-transection and continued daily throughout week 18. Serum and synovial fluid collection, subjective pain scores (lameness, degree of weight bearing, response to joint extension, overall pain score, and effusion score), radiographs, and force plate analyses were all performed prior to CrCL transection, and then at various time points throughout the study until sacrifice at 18 weeks post-transection. At 18 weeks, gross and histologic grading was performed. Immunoassays were performed using the serum and/or synovial fluid in an attempt to determine the level of inflammation (prostaglandin-E2), proteoglycan turnover (sulfated glycosaminoglycans-sGAG), bone formation (bone alkaline phosphatase-BAP, and osteocalcin-OC), collagen synthesis (carboxy-propeptide of type II collagen-CPII), type II collagen degradation (234CEQ neoepitope), type I and II collagen degradation (COL2-3/4Cshort neoepitope), and type I collagen degradation (calculated as COL2-3/4Cshort - 234CEQ). An additional 3 dogs underwent serial arthroscopic examinations of the stifle post-transection. Results. Post-transection arthroscopic examinations demonstrated that articular cartilage and medial meniscal damage started as early as 2 weeks after transection and generally progressed. At 18 weeks, the gross and histologic lesions were highly variable between dogs with respect to incidence, location, severity, and type. Clinical parameters (lameness, degree of weight bearing, joint extension, overall pain score, and effusion score) became significantly worse after transection. PGE2 concentration peaked at 2 weeks and correlated with the peak vertical force and impulse, and subjective lameness and effusion scores. Biomarker analyses demonstrated that type II collagen synthesis and degradation increased after transection, with synthesis predominating early and degradation at the end of the study. Synovial fluid type I collagen degradation was greater than type II collagen, predominating early while type II collagen degradation predominated later. Synovial fluid BAP levels from the operated stifle was significantly correlated to the total radiographic osteophyte score. All analyses did not reveal any significant differences between dogs treated with BAY 12-9566 compared to placebo treated controls. Conclusion. Intra-articular damage starts to occur shortly after arthroscopic CrCL transection and progresses at a highly variable rate such that the MMP inhibitor BAY 12-9566 could not slow down the progression of OA when administered daily from 2 to 18 weeks post-transection. Biomarkers of inflammation, collagen synthesis and degradation, and bone formation can be successfully used in this cruciate-deficient model to characterize sequential patterns of intra-articular damage that occurs.