Jae-Hyuck Shim, Julia F. Charles, Matthew B. Greenblatt, Yeon Suk Yang, Paul B. Yu, Takeshi Takarada, Xianpeng Ge, Hyunho Chun, Wei Gu, Jung-Min Kim, Minkyung Song, Teresa Dinter, Na Li, Odile Filhol-Cochet, Seoyeon Bok, Kwang Hwan Park, Ning Kon, Ren Xu, Brigitte Boldyreff, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Yonsei University College of Medicine [Séoul, Corée du Sud], Xiamen University, Sungkyunkwan University [Suwon] (SKKU), Korea Advanced Institute of Science and Technology (KAIST), Weill Medical College of Cornell University [New York], Harvard Medical School [Boston] (HMS), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), KinaseDetect ApS [Krusa, Danemark], Columbia University College of Physicians and Surgeons, Okayama University Graduate School of Medicine [Okayama, Japon], This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A6A3A03055719, J.M.K.). M.B.G. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a Basil O’Connor Award from the March of Dimes and is supported by an NIH Director’s Early Independence Award (1DP5OD021351), and a Pershing Square Sohn Cancer Research Prize for Young Investigators. J.H.S holds support from NIAMS of the NIH under R01AR068983, R21AR072836, and R21AR073331, an UMCCTS pilot project program award., Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bodescot, Myriam
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., Runx2 is essential for tuning the generation of bone from skeletal stem cells (SSCs). Here, the authors demonstrate that the CK2/HAUSP pathway stabilizes RUNX2 protein thereby regulating the commitment of SSCs to osteoprogenitors as well as their subsequent maturation, and that inhibition of this pathway can block heterotopic ossification.