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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 08, 2020
- Source ID
- 10.1038/s41467-020-16038-6
Entities
People
- Brigitte Boldyreff
- Hyunho Chun
- Jae-Hyuck Shim
- Julia Charles
- Jung-min Kim
- Kwang Hwan Park
- Matthew B Greenblatt
- Minkyung Song
- Na Li
- Ning Kon
- Odile Filhol
- Paul B Yu
- Ren Xu
- Seoyeon Bok
- Takeshi Takarada
- Teresa Dinter
- Wei Gu
- Xianpeng Ge
- Yeon-suk Yang
Organizations
- Burroughs Wellcome Fund
- March of Dimes Canada
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- United States Department of Defense
- United States Department of Health and Human Services