Biomarkers of Cartilage Metabolism and OA

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DESCRIPTION (provided by applicant): Most of what is known about osteoarthrits (OA) has been derived from clinical studies that have focused on the latter stages of this disease, very little is known about its onset and early progression, and by the time its diagnosed, pain and irreparable cartilage damage are present. The mechanism that produces the onset of OA is unclear, it requires time to progress, and the tools necessary to measure the early changes in the biomechanical and biological behavior of articular cartilage have only become available recently. This investigation will be a case-control study of a relatively homogenous group of subjects that can be identified at the time of index anterior cruciate ligament (ACL) trauma and are at significant risk for the post-traumatic onset of OA. The primary aim of the study will be to measure the temporal changes in the concentrations of the biomarkers of articular cartilage metabolism obtained from synovial fluid samples and joint space width narrowing (a validated indicator of progression of OA). These measurements will be made in subjects that plan to undergo ACL reconstruction immediately before surgery, and in matched control subjects with normal knees at the time of recruitment. Measurements will be repeated at the follow-up intervals of 12, 24, and 48-months. These data will be used to test the primary hypothesis: synovial fluid biomarker levels of articular cartilage metabolism (selected to evaluate Type II collagen and proteoglycan) are associated with narrowing of the tibiofemoral joint space. Disruption of the ACL leads to a dramatic increase in anterior-posterior (A-P) knee laxity, joint instability, and although reconstruction of this ligament attempts to re-establish normal joint biomechanics, it often results in an abnormal increase of A-P knee laxity during healing. One mechanism by which ACL injury and reconstruction leads to OA may be explained by a self-perpetuating process in which structural changes within the ACL graft produce increases in A-P knee laxity, abnormal articular cartilage contact stress, abnormal cartilage metabolism, abnormal articular cartilage properties, and eventually loss of this structure. This serves as the basis for our exploratory hypothesis: the relationship between synovial fluid biomarkers of articular cartilage metabolism and narrowing of the tibiofemoral joint space can be explained by increases in A-P knee laxity during healing. This investigation is important because it will validate the use of synovial fluid biomarkers for the study of early progression of post-traumatic OA and provide insight into the relationship between the altered knee biomechanics associated with ACL reconstruction and progression of OA.