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 () and Jae-Hyuck Shim ()
Additional contact information
Jung-Min Kim: University of Massachusetts Medical School
Yeon-Suk Yang: University of Massachusetts Medical School
Kwang Hwan Park: Yonsei University College of Medicine
Xianpeng Ge: University of Massachusetts Medical School
Ren Xu: Xiamen University
Na Li: Xiamen University
Minkyung Song: Sungkyunkwan University
Hyunho Chun: Korea Advanced Institute of Science and Technology
Seoyeon Bok: Weill Cornell Medical College
Julia F. Charles: Brigham and Women’s Hospital, Harvard Medical School
Odile Filhol-Cochet: Commissariat à l’Énergie Atomique et aux Énerigies Alternatives Grenoble
Brigitte Boldyreff: KinaseDetect ApS
Teresa Dinter: Brigham and Women’s Hospital, Harvard Medical School
Paul B. Yu: Brigham and Women’s Hospital, Harvard Medical School
Ning Kon: Institute of Cancer Genetics, College of Physicians and Surgeons of Columbia University
Wei Gu: Institute of Cancer Genetics, College of Physicians and Surgeons of Columbia University
Takeshi Takarada: Okayama University Graduate School of Medicine
Matthew B. Greenblatt: Weill Cornell Medical College
Jae-Hyuck Shim: University of Massachusetts Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16038-6

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