Inhibitory effects ofγ-interferon on bradykinin-induced bone resorption and prostaglandin formation in cultured mouse calvarial bones

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Abstract
The effects of mouse recombinantγ-interferon (γ-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 of45Ca from prelabelled bones as a paramenter of bone resorption. In addition, the effects ofγ-IFN and indomethacin on formation of PGE2 in bone cultures stimulated by bradykinin was analyzed. Indomethacin (1 μmol/l) totally abolished bradykinin (1 μmol/l) induced45Ca release. The inhibitory effect of indomethacin could be fully reversed by addition of PGE2 (1 μmol/l).γ-IFN (1000 U/ml) almost totally inhibited45Ca release stimulated by bradykinin (1 μmol/l), but the inhibitory effect could only be partially overcome by PGE2.γ-IFN and indomethacin also inhibited the stimulatory effects of Lys-bradykinin, Met-Lys-bradykinin and des-Arg9-bradykinin (1 μmol/l) on45Ca release. The stimulatory effects of PGE2 (1 μmol/l) on radioactive calcium mobilization was partially inhibited byγ-IFN (1000 U/ml), whereas indomethacin (1 μmol/l) was without effect. The inhibitory effect ofγ-IFN on45Ca release stimulated by bradykinin and PGE2 was dose-dependent with threshold for action at 3–30 U/ml. Comparative dose-response curves showed thatγ-IFN was most potent as inhibitor of bradykinin induced45Ca release. Bradykinin (1 μmol/l) significantly stimulated PGE2 formation by a mechanism that was completely inhibited by indomethacin (1 μmol/l).γ-IFN (1000 U/ml) partially inhibited the stimulatory effect of bradykinin on PGE2 formation. These data show that i)γ-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 thatγ-IFN can inhibit bone resorption by mechanisms unrelated to prostaglandin formation.

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