Abstract
Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions 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 identified KDM4B as an epigenetic regulator of osteoclast differentiation. Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency. Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. Using genome-wide chromatin immunoprecipitation (ChIP)-sequencing, we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation. We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure (euchromatinization) near the promoters of osteoclast-related genes through H3K9 demethylation, leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65. Finally, small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model. Taken together, our findings establish KDM4B as a critical regulator of osteoclastogenesis, providing a potential therapeutic target for osteoporosis.
Highlights
Bone provides structural support, protects vital organs and tissues, and stores minerals such as calcium and phosphates
Given that KDM4B and CCAR1 are localized in both the cytosol and in the nucleus[41,44] and that RANKL-RANK. These results suggest that Kdm4b loss resulted in a high bone signaling is rapidly transmitted to the nucleus, we speculated that mass phenotype associated with both decreased osteoclast and RANKL-RANK signaling can trigger nuclear accumulation of increased osteoblast activity
Cluster I) mapped to promoters (Fig. 3d). These results indicate strongly indicate that KDM4B and CCAR1 cooperate to upregulate that colocalization of KDM4B and CCAR1 might be functionally target genes by demethylating H3K9me[3] (Fig. 5e)
Summary
Sun-Ju Yi1, You-Jee Jang[2], Hye-Jung Kim[3], Kyubin Lee[1], Hyerim Lee[1], Yeojin Kim[1], Junil Kim[1], Seon Young Hwang[1], Jin Sook Song[4], Hitoshi Okada[5], Jae-Il Park[2], Kyuho Kang 1 and Kyunghwan Kim[1]. Ex vivo deletion of Kdm4b using shRNA and studies in myeloid-specific Kdm4b-deficient transcriptional coactivator by regulating H3K9 methylation.[23,33,38,39] To further understand the biological role of KDM4B mice clearly demonstrated that KDM4B is crucial for osteoclast in euchromatinization, we generated a HeLa cell line stably formation and bone homeostasis These biochemical and genome- expressing KDM4B fused to FLAG and HA epitope tags. To sion of NFATc1 and three of its target genes after RANKL more precisely determine the nature of the association between treatment (Supplementary Fig. 1c) These ex vivo results KDM4B and CCAR1, we performed additional co-IP experiments in suggested that Kdm4b is transcriptionally activated via the cells expressing a series of KDM4B and CCAR1 truncation mutants.
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