FIBRONECTIN-FRAGMENT-INDUCED CARTILAGE CHONDROLYSIS IS ASSOCIATED WITH RELEASE OF CATABOLIC CYTOKINES

Fibronectin fragments have both catabolic and anabolic activities towa rd articular cartilage explants in vitro. Whereas a 1 nM concentration of an N-terminal 29 kDa fibronectin fragment (Fn-f) increases the pro teoglycan (PG) content of cartilage without induction of matrix metall oproteinases (MMPs), 0.1-1 mu M Fn-f temporarily suppresses PG synthes is and enhances MMP release. The higher concentrations cause an initia lly rapid PG depletion during the first week of culture, followed by m uch slower PG loss and gradually increasing rates of PG synthesis. To test for the involvement of mediators, human articular cartilage was c ultured with Fn-f, and conditioned media were assayed for selected cyt okines and factors. With 1 nM Fn-f, the release of the anabolic factor s, insulin growth factor-I and transforming growth factor beta 1, from cultured cartilage was enhanced by 50-100 % during the entire 28-day culture period and this was associated with both supernormal rates of PG synthesis and PG content However, the higher concentrations of Fn-f additionally enhanced release, by at least 10-fold, of the cytokines, tumour necrosis factor alpha, interIeukin-1 alpha, interleukin-1 beta and interleukin-6 while causing depletion of cartilage PG. Release of tumour necrosis factor alpha, interIeukin 1 beta and interleukin la p eaked at days 2, 3 and 9 during or slightly after the period of maxima l PG depletion and decreased to control levels by days 7, 7 and 21 res pectively, whereas release of interleukin 6 was enhanced throughout th e culture period. Neutralizing antibodies to the catabolic cytokines r educed Fn-f-mediated MMP-3 release and suppression of PG synthesis. Th e temporal aspects of this interplay between catabolic and anabolic fa ctors are consistent with the kinetics of Fn-f-mediated cartilage dama ge and attempted repair and may be relevant to cartilage damage and re pair in vivo.