Transection or rupture of the anterior cruciate ligament (ACL) in the human or dog knee joint causes joint instability and predisposes to osteoarthritic changes. The injury leads within 48 hours to a marked increase in the rate of release of aggrecan fragments into the joint fluid. This increase in aggrecan catabolism is accompanied by an increase in aggrecan synthesis and changes in the metabolism of type II collagen. This state of hypermetabolism in the injured knee joint is most pronounced during the first 5 weeks after the insult; although it diminishes in intensity thereafter, it remains elevated for several years. In the dog model of ACL transection (ACLT), a significant elevation in the serum level of antigenic keratan sulfate (KS) occurs reproducibly within 2-3 weeks and remains at a constant high for at least 13 weeks. We have postulated that this reflects a systemic state of aggrecan hypermetabolism involving many cartilages in the body. We propose to test the hypothesis that ACLT triggers an increase in the turnover rate of cartilage aggrecan that is restricted to the injured joint at first but becomes systemic with time. First, we will attempt to obtain evidence that the rise in the level of antigenic KS in canine serum after ACLT truly reflects an increase in the rate of aggrecan catabolism and not changes in either antigenicity of KS or alteration in the kinetics of entry/clearance of KS-bearing fragments in/from different compartments. Second, we will measure marker levels of aggrecan degradation in the contralateral knee and elbow joints before and at various times after injury to test the hypothesis that the ACLT-induced increase int he serum level of antigenic KS in the dog truly does reflect a systemic change occurring in many joints. Third, we will determine if loading of the unstable canine knee plays an essential role in the development and/or persistence of the systemic state of aggrecan hypermetabolism. In addition, we will attempt to identify factors appearing in joint fluid and/or blood after ACLT which can promote the state of hypermetabolism in vitro. Fourth, we will examine if ACLT in the dog also gives rise to changes in the joint fluid, serum and urine levels of other markers of either the synthesis or catabolism of other cartilage-specific molecules, i.e. chondrocalcin, cartilage oligomeric matrix protein, 148 kDa, lysylpyridinoline crosslink. Finally, we will determine if ACL injury in man is accompanied by the same or a different pattern of local and systemic changes in the metabolism of aggrecan and other cartilage-specific molecules as in the dog. These studies will provide important new information about early changes in articular cartilage metabolism in post-traumatic osteoarthritis of the knee and will improve our understanding of the mechanisms responsible for the development and perpetuation of the systemic state of aggrecan hypermetabolism which is prevalent in humans with knee osteoarthritis.