title: Suppression of interleukin-11-mediated bone resorption by cyclooxygenases inhibitors.
abstract: We previously found that human melanoma (A375M) and human breast cancer (MDA-MB-231) cells formed osteolytic bone metastasis in vivo. These cancer cells produced interleukin-11 (IL-11) by themselves and stimulated its production from osteoblasts. Interleukin-11 could increase the number of osteoclasts and raise the calcium concentration in the medium of neonatal murine calvaria organ culture, indicating bone resorption in vitro. Therefore, IL-11 could play an important role in the promotion of osteolysis at the site of bone metastasis. In the present study, we used the calvaria culture system to try to clarify the mechanisms of IL-11-mediated bone resorption. The murine calvaria expressed both the specificity-determining alpha subunit and the signal-transducing beta subunit (gp130) of the IL-11 receptor. When IL-11 was added to the calvaria culture, the concentrations of prostaglandin E2 (PGE2) was elevated. Pretreatment of calvaria with cyclooxygenases inhibitors (e.g., indomethacin, NS-398, and dexamethasone) suppressed the production of PGE2 and the bone resorption induced by IL-11. Addition of exogenous PGE2 overcame the inhibitory effect of cyclooxygenases inhibitors and promoted bone resorption. These results indicate that IL-11 promotes bone resorption through a PGE2 synthesis-dependent mechanism and that cyclooxygenases inhibitors could be interesting drugs to suppress IL-11-mediated osteolytic bone metastasis of cancer cells.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Morinaga
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: K
authors.initials: K
authors.lastname: Ohishi
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000235:genetics; D001862:Bone Resorption; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D050822:Cytokine Receptor gp130; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D006801:Humans; D017370:Interleukin-11 / Q000494:pharmacology*; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000235:genetics; D053702:Receptors, Interleukin-11; D012886:Skull
chemical_list: D015703:Antigens, CD; D016861:Cyclooxygenase Inhibitors; C508428:IL11RA protein, human; C494199:IL6ST protein, human; C508429:Il11ra1 protein, mouse; C508431:Il11ra2 protein, mouse; C494200:Il6st protein, mouse; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D050822:Cytokine Receptor gp130; D015232:Dinoprostone