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Updated: Jun 6, 2025

Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
VprBP regulates osteoclast differentiation via an epigenetic mechanism involving histone H2A phosphorylation
Yonghwan Shin1, Sungmin Kim1, Tae-Ik Choi2
1Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
Background:
Bone remodeling is a continuous and balanced process which relies on the dynamic equilibrium between osteoclastic bone resorption and osteoblastic bone formation. During osteoclast differentiation, pro-osteoclastogenic and anti-osteoclastogenic genes are selectively targeted by positive and negative transcription regulators, respectively. VprBP, also known as DCAF1, is a recently identified kinase and plays an important role in driving epigenetic gene silencing and oncogenic transformation. However, nothing is currently known about a possible involvement of VprBP in signaling pathways that regulate other cellular processes.
Results:
We demonstrate that VprBP stimulates RANKL-induced differentiation of osteoclast precursor cells (OCPs) into mature osteoclasts by suppressing the expression of anti-osteoclastogenic genes through phosphorylation of threonine 120 on histone H2A (H2AT120p). H2AT120p is critical for VprBP function, because abrogating VprBP kinase activity toward H2AT120 transcriptionally reactivates anti-osteoclastogenic genes and significantly attenuates osteoclast differentiation. Consistent with this notion, our in vivo studies established the importance of VprBP-mediated H2AT120p in low bone mass phenotypes and osteoporosis caused by overactive osteoclasts.
Conclusions:
Our data reveal a previously unrecognized function of VprBP in supporting RANKL-induced osteoclast differentiation and the molecular mechanism underlying its action as a negative regulator of anti-osteoclastogenic genes.
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