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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 
 NATURE COMMUNICATIONS, Vol.11(1) : 2289, 2020-05 
Journal Title
Issue Date
Adult ; Aged ; Animals ; Casein Kinase II / genetics ; Casein Kinase II / metabolism ; Cell Differentiation ; Cleidocranial Dysplasia / genetics ; Cleidocranial Dysplasia / pathology ; Core Binding Factor Alpha 1 Subunit / metabolism* ; Female ; Gene Deletion ; Haploinsufficiency / genetics ; Hindlimb / metabolism ; Humans ; Male ; Mice, Inbred C57BL ; Middle Aged ; Ossification, Heterotopic / genetics ; Ossification, Heterotopic / metabolism* ; Ossification, Heterotopic / pathology ; Osteoblasts / metabolism ; Osteogenesis* ; Phosphorylation ; Protein Stability ; RNA, Messenger / genetics ; RNA, Messenger / metabolism ; Ubiquitin-Specific Peptidase 7 / metabolism
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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1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
Yonsei Authors
Park, Kwang Hwan(박광환) ORCID logo https://orcid.org/0000-0002-2110-0559
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