LEUKEMIA INHIBITORY FACTOR (LIF) BINDING-PROTEIN ATTENUATES THE PHLOGISTIC AND ABOLISHES THE CHONDRAL EFFECTS OF LIF IN GOAT JOINTS

Objective. To investigate the ability of murine leukemia inhibitory fa ctor (LIF) binding protein (mLBP) to attenuate the effects of recombin ant human LIF (rhLIF) in goat radiocarpal joints in vivo. Methods. End otoxin-free saline (1 mi) containing either 0.5 or 1 mu g of rhLIF was injected into the left and right radiocarpal joints of male angora go ats. One hour later the right radiocarpal joints were injected with ei ther 1 or 5 mu g of naturally occurring mLBP in 1 mi saline, while the left radiocarpal joints (controls) received 1 mi saline vehicle alone . Gent joints were examined for clinical features of inflammation and synovial fluid (SE) was aspirated on Day 0 (before injection) and Days 3, and 6 postinjection. Leukocyte counts and concentrations of kerata n sulfate were determined in the SF. Proteoglycan synthesis and proteo glycan content of cartilage was determined ex vivo in cartilage explan ts obtained at Day 6. Results. Preliminary time course studies in vitr o showed that mLBP had to be added to cartilage explant cultures withi n 1 h of rhLIF for effective antagonism to occur. In joints injected w ith either 0.5 or 1 mu g rhLIF significant increases in swelling, effu sion volume, leukocyte counts, and SF keratan sulfate concentrations w ere observed relative to controls. Statistically significant depressio ns of ex vivo proteoglycan synthesis and in proteoglycan content of ar ticular cartilage were also observed relative to controls. In joints i njected with 1 mu g rhLIF followed by 1 mu g mLBP, statistically signi ficant improvement was only observed in the rate of ex vivo cartilage proteoglycan synthesis. The observed rate did not differ significantly from that obtained in joints treated with vehicle alone. In contrast, in joints injected with 0.5 mu g rhLIF followed by 5 mu g mLBP, stati stically significant improvement was observed in all variables. Treatm ent with 5 mu g mLBP effectively negated the effects of rhLIF on joint swelling, effusion volume, leukocyte infiltration, and cartilage prot eoglycan catabolism. Conclusion. Murine LBP has the ability to attenua te the phlogistic effects of rhLIF in radiocarpal joints of goats and also abolishes the stimulatory effect of rhLIF on cartilage proteoglyc an catabolism and depression of ex vivo proteoglycan synthesis. These antiinflammatory and chondral effects suggest that a humanized derivat ive of mLBP could be a clinically useful antagonist for LIF in inflamm atory diseases.