KDM4B-CCAR1-Mediator axis is a critical regulator of osteoclast differentiation and bone homeostasis

Bone undergoes a constant and continuous remodeling process which is tightly regulated by the coordinated and the sequential action of bone-resorbing osteoclasts and bone-forming osteoblasts. Recent studies have shown that histone demethylases are implicated in osteoblastogenesis. However, little is known about the role of histone demethylases in osteoclast formation. Here, we identify KDM4B as an epigenetic regulator of osteoclast differentiation.Our biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and Med complex. Using chromatin immunoprecipitation (ChIP) with sequencing, we revealed that KDM4B-CCAR1-Med1 is localized at the promoters of several osteoclast-related genes after RANKL stimulation. We demonstrated that KDM4B-CCAR1-MED1 axis is required for p65 localization at the promoters of osteoclast-related genes through a direct interaction between KDM4B and p65 and changes in chromatin structures (euchromatinization). Finally, small-molecular inhibition of KDM4B impedes bone loss in the ovariectomized mouse model. Taken together, our findings establish KDM4B as a critical regulator of osteoclastogenesis, providing a potential therapeutic target of osteoporosis. Overall design: ChIP-sequencing of KDM4B, CCAR1, MED1 and p65 in BMM cells with RANKL treatment. High-throughput sequencing was performed as single read 75bp sequencing using HigSeq 2500.