Department of Medicine; Li Weibo Institute for Rare Diseases Research
Amino Acids, Peptides, and Proteins | Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Enzymes and Coenzymes | Musculoskeletal System
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.
Bone, Bone development, Trauma, UMCCTS funding
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DOI of Published Version
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
Kim J, Yang Y, Ge X, Greenblatt MB, Shim J. (2020). A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation. Open Access Articles. https://doi.org/10.1038/s41467-020-16038-6. Retrieved from https://escholarship.umassmed.edu/oapubs/4257
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This work is licensed under a Creative Commons Attribution 4.0 License.
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