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dc.contributor.authorMoen, Ingrid Nyhus
dc.contributor.authorWesthrin, Marita
dc.contributor.authorHåland, Erling
dc.contributor.authorHaug, Markus
dc.contributor.authorNonstad, Unni
dc.contributor.authorKlaharn, Merisa
dc.contributor.authorStandal, Therese
dc.contributor.authorStarheim, Kristian K.
dc.date.accessioned2021-09-30T10:26:24Z
dc.date.available2021-09-30T10:26:24Z
dc.date.created2021-09-27T12:20:27Z
dc.date.issued2021
dc.identifier.citationCell death discovery. 2021, 7:36 1-11.en_US
dc.identifier.issn2058-7716
dc.identifier.urihttps://hdl.handle.net/11250/2786546
dc.description.abstractElevated activity of bone-degrading osteoclasts (OC) contributes to pathological bone degradation in diseases such as multiple myeloma. Several proinflammatory cytokines, including TNF, contribute to osteoclastogenesis. The receptor-interacting protein kinase 1 (RIPK1) regulates inflammation and cell death. It is recruited to the TNF-receptor complex, where it is ubiquitinated, and activates transcription factor NF-κB and mitogen-activated protein kinases (MAPK). Smac-mimetics (SM) is a group of drugs that block RIPK1 ubiquitination and shifts RIPK1 to activation of apoptosis or necroptosis. In this manuscript, we show that the two SM birinapant and LCL-161 reduced the number and viability of primary human OC, and induced TNF-dependent cell death in OC precursors (pre-OC). Birinapant was more cytotoxic than LCL-161 and induced predominantly apoptosis and to some degree necroptosis. Both inhibitors restrained osteoclastogenesis induced by myeloma patient bone-marrow aspirates. SM has gained attention as novel treatment strategies both for cancer and chronic inflammatory pathologies, but limited information has been available on interactions with primary human immune cells. As LCL-161 is in phase 2 clinical studies for multiple myeloma, we propose that SM might possess additional benefits in reducing bone degradation in myeloma patients. Taken together, we show that SM reduces human osteoclastogenesis, and that these compounds may represent promising drug candidates for pathological bone degradation.en_US
dc.language.isoengen_US
dc.publisherNature Researchen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleSmac-mimetics reduce numbers and viability of human osteoclastsen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.source.pagenumber1-11en_US
dc.source.volume7:36en_US
dc.source.journalCell death discoveryen_US
dc.identifier.doi10.1038/s41420-021-00415-1
dc.identifier.cristin1939002
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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