Modulation of cartilage proteoglycan metabolism by LIF binding protein

Leukaemia inhibitory factor (LIF) and oncostatin M (OSM) exhibit pleiotropic biological activities, share many structural and genetic features and bind with 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 PG synthesis in cultured pig articular cartilage explants. The aim of this study was to determine whether LBP can block PG resorption and or reverse the inhibition of PG synthesis induced by LIF and OSM. In cultured pig cartilage explants LBP was found to dose dependently inhibit LIF stimulated release of PGs and reverse the suppression of PG synthesis. LBP was found to substantially attenuate the effects of LIF. In contrast only partial inhibition of the stimulatory effect of OSM was observed at the highest concentration of LBP 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 combination of LIF and IL-1 and also OSM and IL-1 did show additive effects in respect to stimulation of PG catabolism and inhibition of PG synthesis. These effects were significantly greater than those observed for LIF, OSM and IL-1 alone. The results suggest that pig articular chondrocytes possess the LIF/OSM receptor, but possibly not an independent OSM receptor. The actions of mLBP indicate that rhLBP could be a clinically useful antagonist for LIF and perhaps OSM.