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Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: Involvement of mevalonate pathway, TNFα, macrophages, and T-cells
- Source :
- International Immunopharmacology. 7:152-161
- Publication Year :
- 2007
- Publisher :
- Elsevier BV, 2007.
-
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.
- Subjects :
- Necrosis
T-Lymphocytes
medicine.medical_treatment
Interleukin-1beta
Immunology
Mevalonic Acid
Spleen
Inflammation
Histidine Decarboxylase
Pharmacology
Mice
Interleukin-1alpha
medicine
Animals
Immunology and Allergy
Lung
Peritoneal Cavity
Mice, Knockout
Alendronate
Bone Density Conservation Agents
Tumor Necrosis Factor-alpha
business.industry
Macrophages
Histidine decarboxylase
medicine.anatomical_structure
Cytokine
Liver
Liposomes
Female
Tumor necrosis factor alpha
Mevalonate pathway
Bone marrow
Clodronic Acid
Hydroxymethylglutaryl-CoA Reductase Inhibitors
medicine.symptom
business
Subjects
Details
- ISSN :
- 15675769
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- International Immunopharmacology
- Accession number :
- edsair.doi.dedup.....7ea9d80758926e13d03ef529ed4693eb