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A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation

Author

Listed:
  • 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
    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
    University of Massachusetts Medical School)

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.

Suggested Citation

  • 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 , 2020. "A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16038-6
    DOI: 10.1038/s41467-020-16038-6
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