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A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling
dc.contributor.authorZhu, Lingxin
dc.contributor.authorTang, Yi
dc.contributor.authorLi, Xiao-Yan
dc.contributor.authorKerk, Samuel A
dc.contributor.authorLyssiotis, Costas A
dc.contributor.authorFeng, Wenqing
dc.contributor.authorSun, Xiaoyue
dc.contributor.authorHespe, Geoffrey E
dc.contributor.authorWang, Zijun
dc.contributor.authorStemmler, Marc P
dc.contributor.authorBrabletz, Simone
dc.contributor.authorBrabletz, Thomas
dc.contributor.authorKeller, Evan T
dc.contributor.authorMa, Jun
dc.contributor.authorCho, Jung-Sun
dc.contributor.authorYang, Jingwen
dc.contributor.authorWeiss, Stephen J
dc.date.accessioned2023-04-04T17:40:38Z
dc.date.available2024-05-04 13:40:27en
dc.date.available2023-04-04T17:40:38Z
dc.date.issued2023-04-03
dc.identifier.citationZhu, Lingxin; Tang, Yi; Li, Xiao-Yan ; Kerk, Samuel A; Lyssiotis, Costas A; Feng, Wenqing; Sun, Xiaoyue; Hespe, Geoffrey E; Wang, Zijun; Stemmler, Marc P; Brabletz, Simone; Brabletz, Thomas; Keller, Evan T; Ma, Jun; Cho, Jung-Sun ; Yang, Jingwen; Weiss, Stephen J (2023). "A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling." The EMBO Journal (7): n/a-n/a.
dc.identifier.issn0261-4189
dc.identifier.issn1460-2075
dc.identifier.urihttps://hdl.handle.net/2027.42/176046
dc.description.abstractOsteoclasts are bone-resorbing polykaryons responsible for skeletal remodeling during health and disease. Coincident with their differentiation from myeloid precursors, osteoclasts undergo extensive transcriptional and metabolic reprogramming in order to acquire the cellular machinery necessary to demineralize bone and digest its interwoven extracellular matrix. While attempting to identify new regulatory molecules critical to bone resorption, we discovered that murine and human osteoclast differentiation is accompanied by the expression of Zeb1, a zinc-finger transcriptional repressor whose role in normal development is most frequently linked to the control of epithelial-mesenchymal programs. However, following targeting, we find that Zeb1 serves as an unexpected regulator of osteoclast energy metabolism. In vivo, Zeb1-null osteoclasts assume a hyperactivated state, markedly decreasing bone density due to excessive resorptive activity. Mechanistically, Zeb1 acts in a rheostat-like fashion to modulate murine and human osteoclast activity by transcriptionally repressing an ATP-buffering enzyme, mitochondrial creatine kinase 1 (MtCK1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration. Together, these studies identify a novel Zeb1/MtCK1 axis that exerts metabolic control over bone resorption in vitro and in vivo.SynopsisOsteoporosis and similar bone-wasting conditions can be caused by an increase in osteoclast-mediated bone resorption. Here, we learn that both murine and human osteoclasts are activated by a Zeb1-dependent regulation of mitochondrial energy metabolism.The transcription factor Zeb1 is a negative regulator of giant multinucleated osteoclast-mediated skeletal remodeling.Zeb1 regulates mitochondrial energy metabolism in myeloid lineage-derived osteoclasts.The mitochondrial creatine kinase MtCK1 is a transcriptional target of Zeb1 that enables bone resorption by buffering ATP availability.The transcription factor Zeb1 influences bone development by regulating mitochondrial ATP availability.
dc.publisherWiley Periodicals, Inc.
dc.subject.othermitochondrial creatine kinase
dc.subject.otherskeletal remodeling
dc.subject.otherZeb1
dc.subject.otherbone resorption
dc.subject.otherosteoclast
dc.titleA Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biology
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/176046/1/embj2022111148_1.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/176046/2/embj2022111148-sup-0002-EVFigs.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/176046/3/embj2022111148.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/176046/4/embj2022111148-sup-0001-Appendix.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/176046/5/embj2022111148.reviewer_comments.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/176046/6/embj2022111148_am.pdf
dc.identifier.doi10.15252/embj.2022111148
dc.identifier.sourceThe EMBO Journal
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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