UMMS Affiliation

Department of Medicine; Li Weibo Institute for Rare Diseases Research

Publication Date

2020-05-08

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Enzymes and Coenzymes | Musculoskeletal System

Abstract

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.

Keywords

Bone, Bone development, Trauma

Rights and Permissions

© 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/.

DOI of Published Version

10.1038/s41467-020-16038-6

Source

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. Link to article on publisher's site

Journal/Book/Conference Title

Nature communications

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

32385263

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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