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.
Highlights
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 overexuberant osteogenesis results in heterotopic ossification (HO) of soft tissues
A high-throughput short hairpin RNA screen was performed in human bone marrow-derived mesenchymal stromal cells (BMSCs) using an alkaline phosphatase (ALP) assay, a marker of early osteoblast differentiation in order to identify kinases and/or phosphatases required for osteoblast differentiation[34,35]
While the human SSCs serving as a source of osteoblasts after growth plate closure are currently unclear, we noted the presence of cells bearing the same surface immunophenotype as previously described murine SSCs (Lin-Thy-CD200 + CD105- cells)[3,36] present in bone marrow aspirates (BMA)
Summary
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 overexuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. 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. Active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization As shown by both disorders of inappropriate bone formation, such as heterotopic ossification (HO) and disorders of deficient bone formation, such as osteoporosis, the capacity of skeletal stem cells (SSCs) to differentiate into boneforming osteoblasts must be tuned in a context and tissue dependent manner. We demonstrate that CK2-induced phosphorylation of RUNX2 recruits the deubiquitinase HAUSP for the stabilization of RUNX2 and that this pathway is required for physiologic and pathologic bone formation
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