The KDM4B–CCAR1–MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis

查看全文 作　　者：Sun-Ju [1]Yi;You-Jee [2]Jang;Hye-Jung [3]Kim;Kyubin [1]Lee;Hyerim [1]Lee;Yeojin [1]Kim;Junil [1]Kim;Seon Young [1]Hwang;Jin Sook [4]Song;Hitoshi [5]Okada;Jae-Il [2]Park;Kyuho [1]Kang;Kyunghwan [1]Kim

机构地区：[1]Department of Biological Sciences and Biotechnology,Chungbuk National University,Cheongju,Chungbuk,Republic of Korea;[2]Korea Basic Science Institute,Gwangju Center at Chonnam National University,Gwangju,Republic of Korea;[3]New Drug Development Center,KBIO Osong Medical Innovation Foundation,Cheongju,Chungbuk,Republic of Korea;[4]Data Convergence Drug Research Center,Therapeutics&Biotechnology Division,Korea Research Institute of Chemical Technology,Daejeon,Republic of Korea;[5]Department of Biochemistry,Kindai University Faculty of Medicine,Osakasayama,Osaka,Japan

出　　处：《Bone Research》索引2021年第9卷第3期,共13页

基　　金：support of the National Research Foundation of Korea(2017R1C1B2008017,2020R1A6A1A06046235,and 2020R1A2C1008179 to K.K.,2019R1I1A1A01061125 to S.J.Y.). 摘　　要：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. 关键词：formation. CRITICAL MED1

相关文献

参考文献（57）
引证文献（2）
耦合文献（74）

参考文献(57)

引证文献(2)

耦合文献(74)

互联网出版许可证新出网证(渝)字10号全国400电话 - 免长途话费

The KDM4B–CCAR1–MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis

参考文献(57)

引证文献(2)

耦合文献(74)

用户提示