SUPPRESSION OF INTERLEUKIN-11-MEDIATED BONE-RESORPTION BY CYCLOOXYGENASES INHIBITORS

We previously found that human melanoma (A375M) and human breast cance r (MDA-MB-231) cells formed osteolytic bone metastasis in vivo. These cancer cells produced interleukin-11 (IL-11) by themselves and stimula ted its production from osteoblasts. Interleukin-ll could increase the number of osteoclasts and raise the calcium concentration in the medi um of neonatal murine calvaria organ culture, indicating bone resorpti on in vitro. Therefore, IL-ll could play an important role in the prom otion of osteolysis at the site of bone metastasis. in the present stu dy, we used the calvaria culture system to try to clarify the mechanis ms of IL-ll-mediated bone resorption. The murine calvaria expressed bo th the specificity-determining oc subunit and the signal-transducing b eta subunit (gp130) of the IL-ll receptor. When IL-ll was added to the calvaria culture, the concentrations of prostaglandin E-2 (PGE(2)) wa s elevated. Pretreatment of calvaria with cyclooxygenases inhibitors ( e.g., indomethacin, NS-398, and dexamethasone) suppressed the producti on of PGE, and the bone resorption induced by IL-11. Addition of exoge nous PGE, overcame the inhibitory effect of cyclooxygenases inhibitors and promoted bone resorption. These results indicate that IL-l 1 prom otes bone resorption through a PGE, synthesis-dependent mechanism and that cyclooxygenases inhibitors could be interesting drugs to suppress IL-11-mediated osteolytic bone metastasis of cancer cells. (C) 1998 W iley-Liss, Inc.