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dc.contributor.authorRogers, Michael J
dc.contributor.authorMönkkönen, Jukka
dc.contributor.authorMunoz, Marcia A
dc.date.accessioned2020-09-21T11:44:34Z
dc.date.available2020-09-21T11:44:34Z
dc.date.issued2020
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/8323
dc.description.abstractBisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act by selectively targeting bone-resorbing osteoclasts and can be grouped into two classes depending on their intracellular mechanisms of action. Simple BPs cause osteoclast apoptosis after cytoplasmic conversion into toxic ATP analogues. In contrast, nitrogen-containing BPs potently inhibit FPP synthase, an enzyme of the mevalonate (cholesterol biosynthesis) pathway. This results in production of a toxic metabolite (ApppI) and the loss of long-chain isoprenoid lipids required for protein prenylation, a process necessary for the function of small GTPase proteins essential for the survival and activity of osteoclasts. In this review we provide a state-of-the-art overview of these mechanisms of action and a historical perspective of how they were discovered. Finally, we challenge the long-held dogma that BPs act only in the skeleton and highlight recent studies that reveal insights into hitherto unknown effects on tumour-associated and tissue-resident macrophages.
dc.language.isoenglanti
dc.publisherElsevier BV
dc.relation.ispartofseriesBone
dc.relation.urihttp://dx.doi.org/10.1016/j.bone.2020.115493
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectbisphosphonate
dc.subjectbone resorption
dc.subjectosteoclast
dc.subjectmevalonate
dc.subjectisoprenoid
dc.subjectfarnesyl
dc.subjectgeranylgeranyl
dc.subjectFPP
dc.subjectGGPP
dc.subjectIPP
dc.subjectsmall GTPase
dc.subjectprenylation
dc.subjectclodronate
dc.subjectzoledronate
dc.subjectmacrophage
dc.subjectγ,δ-T cell
dc.titleMolecular Mechanisms of Actions of Bisphosphonates and New Insights Into Their Effects Outside the Skeleton
dc.description.versionfinal draft
dc.contributor.departmentSchool of Pharmacy, Activities
uef.solecris.id71526183en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© 2020 Published by Elsevier Inc.
dc.relation.doi10.1016/j.bone.2020.115493
dc.description.reviewstatuspeerReviewed
dc.relation.articlenumber115493
dc.relation.issn8756-3282
dc.relation.volume139
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessEi


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