title: Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: involvement of mevalonate pathway, TNFalpha, macrophages, and T-cells.
abstract: Nitrogen-containing bisphosphonates (NBPs) are powerful anti-bone-resorptive drugs, but they frequently induce various inflammatory side effects. Recent clinical applications have disclosed an unexpected new side effect, jaw-bone necrosis and exposure. In vitro studies suggest that the inflammatory effects of NBPs are due to Vgamma2Vdelta2 T-cells, stimulated directly and/or indirectly [the latter via isopentenylpyrophosphate (IPP) in the mevalonate pathway]. Rats and mice, however, lack Vgamma2Vdelta2 T-cells, yet NBPs still induce necrotic and inflammatory reactions. In mice, NBPs induce IL-1-dependent inflammatory reactions, such as inductions of histidine decarboxylase (HDC, the histamine-forming enzyme) in the liver, lung, spleen, and bone marrow, an increase in granulocytic cells in the peritoneal cavity, pleural exudation, and splenomegaly. Here, we examined the involvement of IPP, TNF, macrophages, and T-cells in the inflammatory actions of alendronate (a typical NBP) in mice. Various statins (mevalonate-synthesis inhibitors) suppressed the alendronate-induced HDC inductions, while mevalonate itself augmented such inductions. IPP injection also induced HDC. Like IL-1-deficient mice, TNF-deficient mice were resistant to alendronate-stimulated HDC induction. Alendronate-stimulated HDC inductions were significantly weaker in macrophage-depleted mice and in nude mice than in control mice. Similar, though generally less clear-cut, results were obtained when other alendronate-induced inflammatory reactions were examined. These results suggest that (i) inhibition of the mevalonate pathway causes and/or modifies at least some inflammatory actions of alendronate in mice, (ii) in addition to IL-1, TNF is also involved in the inflammatory actions of alendronate, and (iii) alendronate may act on a variety of cells, including macrophages and T-cells.
authors.affiliation: Department of Molecular Regulation, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-Machi, Sendai, Japan.
authors.forename: Xue
authors.initials: X
authors.lastname: Deng
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Yu
authors.forename: Hiromi
authors.initials: H
authors.lastname: Funayama
authors.forename: Kouji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasano
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D004002:Clodronic Acid / Q000494:pharmacology; D005260:Female; D006640:Histidine Decarboxylase / Q000276:immunology / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010529:Peritoneal Cavity / Q000166:cytology; D013154:Spleen / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D050071:Bone Density Conservation Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D006640:Histidine Decarboxylase; D008798:Mevalonic Acid; D019386:Alendronate