MODULATION OF CARTILAGE PROTEOGLYCAN METABOLISM BY LIF BINDING-PROTEIN

Leukaemia inhibitory factor (LIF) and oncostatin M (OSM) exhibit pleio tropic biological activities, share many structural and genetic featur es and bind,vith high affinity to the same receptor (LIF/OSM receptor) . A soluble form of the LIF-R alpha, called LIF binding protein (LBP) has been isolated from mouse serum. LIF and OSM stimulate proteoglycan (PG) release and inhibit PC synthesis in cultured pig articular carti lage explants, The aim of this study,vas to determine whether LBP can block PG resorption and or reverse the inhibition of PG synthesis indu ced by LIF and OSM. In cultured pig cartilage explants LBP was found t o dose dependently inhibit LIF stimulated release of PCs and reverse t he suppression of PC synthesis, LBP was found to substantially attenua te the effects of LIF, In contrast only partial inhibition of the stim ulatory effect of OSM was observed at the highest concentrations of LB P available. At maximal concentrations, LBP produced minimal reversal of OSM mediated inhibition of PG synthesis. When tested in combination LIF and OSM had no additive effects on PG metabolism, but the combina tion of LIF and IL-1 and also OSM and IL-1 did show additive effects i n respect to stimulation of PG catabolism and inhibition of PC synthes is. These effects mere significantly greater than those observed for L IF, OSM and IL-1 alone. The results suggest that pig articular chondro cytes possess the LIF/OSM receptor, but possibly not an independent OS M receptor. The actions of mLBP indicate that rhLBP could be a clinica lly useful antagonist for LIF and perhaps OSM. (C) 1998 Academic Press Limited.