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

doi:10.1038/s41467-020-16038-6

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

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38 Citations (Scopus)

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.

Original language	English
Article number	2289
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16038-6
Publication status	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Kim, J. M., Yang, Y. S., Park, K. H., Ge, X., Xu, R., Li, N., Song, M., Chun, H., Bok, S., Charles, J. F., Filhol-Cochet, O., Boldyreff, B., Dinter, T., Yu, P. B., Kon, N., Gu, W., Takarada, T., Greenblatt, M. B., & Shim, J. H. (2020). A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation. Nature communications, 11(1), [2289]. https://doi.org/10.1038/s41467-020-16038-6

Kim, JM, Yang, YS, Park, KH, Ge, X, Xu, R, Li, N, Song, M, Chun, H, Bok, S, Charles, JF, Filhol-Cochet, O, Boldyreff, B, Dinter, T, Yu, PB, Kon, N, Gu, W, Takarada, T, Greenblatt, MB & Shim, JH 2020, 'A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation', Nature communications, vol. 11, no. 1, 2289. https://doi.org/10.1038/s41467-020-16038-6

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title = "A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation",

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.",

author = "Kim, {Jung Min} and Yang, {Yeon Suk} and Park, {Kwang Hwan} and Xianpeng Ge and Ren Xu and Na Li and Minkyung Song and Hyunho Chun and Seoyeon Bok and Charles, {Julia F.} and Odile Filhol-Cochet and Brigitte Boldyreff and Teresa Dinter and Yu, {Paul B.} and Ning Kon and Wei Gu and Takeshi Takarada and Greenblatt, {Matthew B.} and Shim, {Jae Hyuck}",

note = "Funding Information: We would like to thank Drs Renny Francheschi, Laurie Glimcher, Sarah Bettigole, and Ellen Gravallese for helpful discussion and Drs Douglas Ballon and Bin He of the Citigroup Biomedical Imaging Core of Weill Cornell Medicine for assistance with microCT imaging. We also thank the many individuals who provided valuable reagents. 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{\textquoteright}Connor Award from the March of Dimes and is supported by an NIH Director{\textquoteright}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. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-16038-6",

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AU - Kim, Jung Min

AU - Yang, Yeon Suk

AU - Park, Kwang Hwan

AU - Ge, Xianpeng

AU - Xu, Ren

AU - Li, Na

AU - Song, Minkyung

AU - Chun, Hyunho

AU - Bok, Seoyeon

AU - Charles, Julia F.

AU - Filhol-Cochet, Odile

AU - Boldyreff, Brigitte

AU - Dinter, Teresa

AU - Yu, Paul B.

AU - Kon, Ning

AU - Gu, Wei

AU - Takarada, Takeshi

AU - Greenblatt, Matthew B.

AU - Shim, Jae Hyuck

N1 - Funding Information: We would like to thank Drs Renny Francheschi, Laurie Glimcher, Sarah Bettigole, and Ellen Gravallese for helpful discussion and Drs Douglas Ballon and Bin He of the Citigroup Biomedical Imaging Core of Weill Cornell Medicine for assistance with microCT imaging. We also thank the many individuals who provided valuable reagents. 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. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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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A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation

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