We have reported that fibronectin fragments (Fn-f) cause cartilage damage in vitro by causing enhanced release of proteases. In order to determine whether the Fn-f can damage cartilage in vivo, we have injected native fibronectin (Fn) and Fn-f into adolescent rabbit knee joints. After 7 days, tissue was analyzed by histochemical and biochemical techniques and remaining proteoglycans quantified. Injection of 0.6 or 3 microM Fn-f caused up to a 70% loss in total cartilage proteoglycan while native Fn, rabbit serum albumin or an Arg-Gly-Asp-Ser synthetic peptide, derived from the cell-binding domain of Fn, did not cause damage. Our results suggest that this Fn-f/damage model may be useful for generating cartilage damage in vivo for other studies. Since Fn-f have been detected in synovial fluids from joints of patients with rheumatoid arthritis and osteoarthritis, our results are consistent with the notion that Fn-F mediated damage may occur in vivo.