Severe damage to cartilage from blunt trauma is thought to trigger a degenerative cascade thatleads to post-traumatic osteoarthritis (PTOA). Cartilage degeneration in PTOA initiates at injurysites and, over a period of years, spreads to engulf previously healthy cartilage. It seems likely thatthis slowly advancing process of local chondrolysis starts with catabolic factors produced at injurysites, but it is not clear how chondrolytic activity is sustained and how lesions spread over such longtime frames. Although this is obviously a multifactorial process influenced substantially by post-trauma mechanical conditions (Project 2), the hypothesis that proteolytic fragments of the cartilageextracellular matrix (ECM) play a role is well-supported by in vitro and in vivo studies. These showthat ECM fragments with strong catabolic effects are enriched in arthritic cartilage and joint fluidsand that their removal from joints inhibits the progression of arthritis. ECM fragments are capableof limited diffusion through normal cartilage and can induce matrix protease expression bychondrocytes deep in the tissue. The potential to create new zones of degeneration and ECMfragmentation suggests a vicious cycle that could lead to sustained chondrolytic activity aroundinjury sites. Here we propose to evaluate the role of ECM fragments in this process, focusing onfibronectin fragments as a likely source of catabolic stimulation in this context. An in vitro cartilageinjury model was developed to study these local catabolic processes. We expect that themechanisms of post-traumatic chondrolysis in this in vitro system will reflect processes that occur invivo, however, this assumption will be tested in an animal cartilage trauma model. These systemswill be used to test the following hypotheses: (1) Fibronectin fragments (Fn-fs) generated at impactinjury sites, stimulate chondrolysis in healthy cartilage; (2) Post-traumatic chondrolysis is self-sustaining and propagates over time; (3) Inhibitors of Fn-f-induced signaling will impede post-traumatic chondrolysis; (4) Post-traumatic chondrolysis is driven by factors intrinsic to cartilage. Atthe conclusion of this project we expect to have identified one or more inhibitors that show strongchondroprotective activity, providing a sound basis for further tests to determine their therapeuticvalue.
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