UC San Diego

Post-traumatic osteoarthritis (PTOA) involves the deterioration of articular cartilage (AC) that typically is triggered by mechanical overload and progresses over decades. Normally, AC forms an effective load-bearing and lubricated surface through a dense network of proteoglycan and collagen and adsorbed friction-lowering molecules, which prevent the tissue from experiencing pathophysiological strains. In PTOA, AC damage ensues, with proteoglycan loss, collagen network disruption, and surface fibrillation and fissures. Also, chondrocytes, cartilage resident cells, undergo necrosis/apoptosis, as well as proliferation and clustering. While AC degeneration may be driven by mechanical factors or enzymatic degradation of the matrix, how joint injuries, such as anterior cruciate ligament (ACL) rupture, cause such tissue damage and elicit a chondrocyte response in PTOA is unclear. This dissertation aimed to determine, in a series of in vivo and in vitro studies, how altered biomechanics may drive cartilage surface damage initiation and progression and chondrocyte proliferative responses. In vivo, after ACL transection in the rabbit, the effect of injecting lubricant molecules on cartilage surface damage was investigated. However, regardless of lubricant treatment, AC surface deteriorated in ACL transected rabbit knees concomitant with reduced chondrocyte density in weight bearing femoral condyles and clustering nearby. In vitro in a post-mortem rabbit condyle-scale loading model, patterns and progressive states of cracks associated with high sliding in ACL deficiency were assessed. In vitro, cracks induced on the AC surface under ACLT-mimicking cyclic loading were progressive, with in vivo-like patterns characteristic of PTOA. With immature cartilage explants in vitro, a method to localize and quantify activated proliferating chondrocytes in situ using EdU was developed. Proliferating cells were identified especially in the superficial zone, where chondroprogenitor cells have been localized. In both normal and OA adult human AC explants in vitro, chondrocyte proliferation was induced either by sequential enzyme treatment or by overloading in unconfined compression after subsequent culture. The above studies further establish abnormal knee biomechanics as a cause of AC degeneration in PTOA and suggest that joint restabilization should be prioritized in conjunction with other chondroprotective treatments. The induction and localization of chondrocyte proliferation in situ provides an additional approach into the biology of both cartilage growth and OA. Controlled human cartilage explant digestion may be useful not only as a model for studying OA, but also as an improved tissue-laden cell source for cartilage repair surgeries.