한빛사 논문
Jung-Min Kim1, Yeon-Suk Yang1, Kwang Hwan Park2, Xianpeng Ge1, Ren Xu3, Na Li3, Minkyung Song4, Hyunho Chun5, Seoyeon Bok6, Julia F. Charles7, Odile Filhol-Cochet8, Brigitte Boldyreff9, Teresa Dinter10, Paul B. Yu10, Ning Kon11, Wei Gu11,12, Takeshi Takarada13, Matthew B. Greenblatt6,* & Jae-Hyuck Shim1,14,*
1Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
2Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, South Korea.
3State Key Laboratory of Cellular Stress Biology, Xiamen University, Fujian, China.
4Department of integrative biotechnology, Sungkyunkwan University, Suwon, South Korea.
5Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
6Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
7Department of Orthopedics and Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
8INSERM U1036, pour le Vivant/Biologie du Cancer et de l’Infection, Commissariat àl’É nergie Atomique et aux É nerigies Alternatives Grenoble, Grenoble, France.
9KinaseDetect ApS, 6340 Krusaa, Denmark.
10Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
11Institute of Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
12Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
13Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan.
14Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA.
*Corresponding author
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.
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