Show simple item record

A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation

dc.contributor.authorKim, Jung-Min
dc.contributor.authorYang, Yeon-Suk
dc.contributor.authorGe, Xianpeng
dc.contributor.authorGreenblatt, Matthew B.
dc.contributor.authorShim, Jae-Hyuck
dc.date2022-08-11T08:09:56.000
dc.date.accessioned2022-08-23T16:49:31Z
dc.date.available2022-08-23T16:49:31Z
dc.date.issued2020-05-08
dc.date.submitted2020-06-16
dc.identifier.citation<p>Kim JM, Yang YS, Park KH, Ge X, Xu R, Li N, Song M, Chun H, Bok S, Charles JF, Filhol-Cochet O, Boldyreff B, Dinter T, Yu PB, Kon N, Gu W, Takarada T, Greenblatt MB, Shim JH. A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation. Nat Commun. 2020 May 8;11(1):2289. doi: 10.1038/s41467-020-16038-6. PMID: 32385263; PMCID: PMC7210266. <a href="https://doi.org/10.1038/s41467-020-16038-6">Link to article on publisher's site</a></p>
dc.identifier.issn2041-1723 (Linking)
dc.identifier.doi10.1038/s41467-020-16038-6
dc.identifier.pmid32385263
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41478
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractThe osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32385263&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights© The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBone
dc.subjectBone development
dc.subjectTrauma
dc.subjectUMCCTS funding
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.subjectDevelopmental Biology
dc.subjectEnzymes and Coenzymes
dc.subjectMusculoskeletal System
dc.titleA RUNX2 stabilization pathway mediates physiologic and pathologic bone formation
dc.typeJournal Article
dc.source.journaltitleNature communications
dc.source.volume11
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5276&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4257
dc.identifier.contextkey18127125
refterms.dateFOA2022-08-23T16:49:31Z
html.description.abstract<p>The osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization.</p>
dc.identifier.submissionpathoapubs/4257
dc.contributor.departmentLi Weibo Institute for Rare Diseases Research
dc.contributor.departmentDepartment of Medicine
dc.source.pages2289


Files in this item

Thumbnail
Name:
s41467_020_16038_6.pdf
Size:
5.749Mb
Format:
PDF
Download

This item appears in the following Collection(s)

Show simple item record

© The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Except where otherwise noted, this item's license is described as © The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.