LEUKEMIA INHIBITORY FACTOR STIMULATES PROTEOGLYCAN RESORPTION IN PORCINE ARTICULAR-CARTILAGE

Leukaemia inhibitory factor (LIF) is a secretory glycoprotein produced by tumour, mesenchymal and haemopoietic cells. LIF has been found to have pleiotropic actions that include the capacity to regulate cell di fferentiation, promote acute-phase protein synthesis and stimulate cal cium release in bone explants. In view of its similarity to other cyto kines that affect cartilage metabolism, the effects of LIF on proteogl ycan resorption were examined in pig cartilage explants. Endotoxin-fre e recombinant mouse LIF was found to produce a dose-dependent increase in sulphated glycosaminoglycan (S-GAG) release (ED50 = 123 U/ml, appr ox. 25 - 50 pM). Statistically significant stimulation was observed wi th doses of 100 U/ml or greater. When pig cartilage was stimulated wit h maximum concentrations of LIF and either interleukin 1alpha (IL-1alp ha), interleukin 1beta (IL-1beta) or tumour necrosis factor alpha (TNF alpha), in each case a significantly greater release of S-GAGs was obs erved than with the respective cytokines alone (P < 0.05). Comparison of the areas under the curves showed that the action of LIF was additi ve, and not synergistic with other catabolic cytokines. Dose-response studies showed that transforming growth factor beta (TGFbeta) produced a partial inhibition of LIF-stimulated release of S-GAGs (ED50 = 4.5 U/ml). Statistically significant inhibition was observed with doses of 2 U/ml or greater. These results showed that LIF stimulated proteogly can resorption in vitro and that this effect was modulated by other cy tokines. Whether LIF contributes to the progressive destruction of car tilage in septic or chronic inflammatory arthritis remains to be deter mined.