INHIBITORY EFFECTS OF GAMMA-INTERFERON ON BRADYKININ-INDUCED BONE-RESORPTION AND PROSTAGLANDIN FORMATION IN CULTURED MOUSE CALVARIAL BONES

The effects of mouse recombinant gamma-interferon (gamma-IFN) and indomethacin on bone resorption stimulated by bradykinin, Lys-bradykinin, Met-Lys-bradykinin, des-Arg9-bradykinin and prostaglandin E2 (PGE2) have been studied using cultures of neonatal calvarial bones and analyzing the release of Ca-45 from prelabelled bones as a paramenter of bone resorption. In addition, the effects of gamma-IFN and indomethacin on formation of PGE2 in bone cultures stimulated by bradykinin was analyzed. Indomethacin (1-mu-mol/l) totally abolished bradykinin (1-mu-mol/l) induced Ca-45 release. The inhibitory effect of indomethacin could be fully reversed by addition of PGE2 (1-mu-mol/l). gamma-IFN (1000 U/ml) almost totally inhibited Ca-45 release stimulated by bradykinin (1-mu-mol/l), but the inhibitory effect could only be partially overcome by PGE2. gamma-IFN and indomethacin also inhibited the stimulatory effects of Lys-bradykinin, Met-Lys-bradykinin and des-Arg9-bradykinin (1-mu-mol/l) on Ca-45 release. The stimulatory effects of PGE2 (1-mu-mol/l) on radioactive calcium mobilization was partially inhibited by gamma-IFN (1000 U/ml), whereas indomethacin (1-mu-mol/l) was without effect. The inhibitory effect of gamma-IFN on Ca-45 release stimulated by bradykinin and PGE2 was dose-dependent with threshold for action at 3-30 U/ml. Comparative dose-response curves showed that gamma-IFN was most potent as inhibitor of bradykinin induced Ca-45 release. Bradykinin (1-mu-mol/l) significantly stimulated PGE2 formation by a mechanism that was completely inhibited by indomethacin (1-mu-mol/l). gamma-IFN (1000 U/ml) partially inhibited the stimulatory effect of bradykinin on PGE2 formation. These data show that i) gamma-IFN is a potent inhibitor of bone resorption induced by bradykinin and bradykinin analogues and ii) that the mechanism of action can be mainly explained by an inhibition of kinin induced prostaglandin biosynthesis. The results, however, also show that gamma-IFN can inhibit bone resorption by mechanisms unrelated to prostaglandin formation.