Restitution of Lubrication in ACL Deficient Joints Preventing Wear

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DESCRIPTION (provided by applicant): Injury is a well established risk factor in the pathogenesis of osteoarthritis (OA). Several large longitudinal population studies support this observation based upon patient history and retrospective data collection instruments. However, efforts to identify patients at risk of progression have been limited. We posit that patients with acute knee injuries and resultant inflammation are at risk for chronic joint complaints. These patients present to emergency departments and manifest an acute traumatic synovitis (TS) secondary to structural defects such as acute anterior cruciate ligament (ACL) injuries following trauma. Both immunologic and mechanical assays have documented a variable lack of lubricin in synovial fluid following injury in both humans and animal models. The presumable result of enhanced cartilaginous wear is supported by recent observations in lubricin (PRG4) null mice which have a normal articular surface at birth and, by contrast, surface fibrillation after weight bearing begins. Lubricin and superficial zone protein (SZP) are the boundary lubricants of articular cartilage- a lubrication mechanism which arises in the absence of viscosity. Diarthrodial joint inflammation results in protease expression which easily catabolizes lubricin/SZP. Progress has been made in identifying the enzymes which initiate this destruction. We propose 3 interconnecting specific aims engaging patients with ACL injuries and a corresponding animal model to better understand synovial homeostasis as it relates to lubrication and by extension chondroprotection. Aim 1: To investigate the early effects of an ACL injury accompanied by mild inflammation on lubricating mechanisms mediated by lubricin in a mammalian joint. Aim 2: Determine if blocking the effects of TNF-a through the administration of a TNF-a inhibitor partially restores the lubricating ability of diarthrodial joints following ACL injury. Aim 3: Synovial fluid aspirates from patients with acute ACL injuries will be analyzed for lubricin levels, lubricin degradation products and its relationship to IL-1b and TNF-a levels. PUBLIC HEALTH RELEVENCE: Injury is a well-established risk factor in the pathogenesis of osteoarthritis (OA). We hypothesize that mammalian joints with acute knee injuries and resultant inflammation are at risk for chronic joint complaints as a result of catabolism of lubricin. This protein serves to protect cartilage from the high load and slow sliding speeds, which characterize movements of these joints at the nanoscale. We also hypothesize that blocking the effects of TNF-a through the administration of a TNF-a inhibitor (Enbrel) partially restores the lubricating ability of diarthrodial joints following ACL injury.