title: Inhibition of mevalonate pathway is involved in alendronate-induced cell growth inhibition, but not in cytokine secretion from macrophages in vitro.
abstract: Bisphosphonates are antiresorptive drugs used for the treatment of metabolic bone diseases. They can be divided into two different pharmacological classes: nitrogen-containing and non-nitrogen-containing bisphosphonates. Non-nitrogen-containing bisphosphonates, like clodronate, are metabolised to a toxic ATP-analogue preventing osteoclast mediated bone resorption. Nitrogen-containing bisphosphonates, including alendronate, prevent osteoclast function by inhibiting the mevalonate pathway. Clodronate is known to have anti-inflammatory properties while alendronate induces cytokine secretion from lipopolysaccharide- (LPS) induced macrophages. This study investigates whether the cytotoxicity and cytokine production induced by alendronate and LPS could be counteracted by clodronate or products of mevalonate pathway: oxidized low density lipoprotein (ox-LDL), farnesol and geranylgeraniol. Treatment with alendronate increased LPS-induced secretion of IL-1beta, IL-6 and TNF-alpha from RAW 264 macrophages 2.4-, 1.4- and 1.8-fold, respectively. This treatment was cytotoxic for macrophages as indicated by lowered cell viability. Clodronate and ox-LDL both counteracted the cytokine secretion and cytotoxicity of alendronate. Farnesol and geranylgeraniol did neither reverse the cytokine secretion nor reduce the cytotoxicity of alendronate. Clodronate and ox-LDL were able to counteract the effects of alendronate on macrophages in vitro, probably by their known ability to inhibit DNA binding activity of transcription factors, nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1). These findings suggest that inhibition of mevalonate pathway is not the mechanism responsible for the proinflammatory response caused by alendronate, as it is in alendronate-induced apoptosis and prevention of osteoclast function.
authors.affiliation: Department of Pharmaceutics, University of Kuopio, PO Box 1627, FIN-70211, Kuopio, Finland. anu.toyras@uku.fi
authors.forename: Anu
authors.initials: A
authors.lastname: Töyräs
authors.forename: Jouko
authors.initials: J
authors.lastname: Ollikainen
authors.forename: Markku
authors.initials: M
authors.lastname: Taskinen
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004224:Diterpenes / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice
chemical_list: D004224:Diterpenes; D008070:Lipopolysaccharides; D005204:Farnesol; C017338:geranylgeraniol; D008798:Mevalonic Acid; D019386:Alendronate