VprBP regulates osteoclast differentiation via an epigenetic mechanism involving histone H2A phosphorylation.

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.