A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation

Jung Min Kim, Yeon Suk Yang, Kwang Hwan Park, Xianpeng Ge, Ren Xu, Na Li, Minkyung Song, Hyunho Chun, Seoyeon Bok, Julia F. Charles, Odile Filhol-Cochet, Brigitte Boldyreff, Teresa Dinter, Paul B. Yu, Ning Kon, Wei Gu, Takeshi Takarada, Matthew B. Greenblatt, Jae Hyuck Shim

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number2289
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Kim, J. M., Yang, Y. S., Park, K. H., Ge, X., Xu, R., Li, N., Song, M., Chun, H., Bok, S., Charles, J. F., Filhol-Cochet, O., Boldyreff, B., Dinter, T., Yu, P. B., Kon, N., Gu, W., Takarada, T., Greenblatt, M. B., & Shim, J. H. (2020). A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation. Nature communications, 11(1), [2289]. https://doi.org/10.1038/s41467-020-16038-6