title: Decitabine represses osteoclastogenesis through inhibition of RANK and NF-κB.
abstract: DNA methylation is essential for maintenance of stable repression of gene transcription during differentiation and tumorigenesis. Demethylating reagents including decitabine could release the repression, leading to perturbed transcription program. Recently others and we showed that, in B cell lymphomas, decitabine repressed B cell specific gene transcription and activated NF-κB signaling, causing decreased expression of translocated oncogenes including MYC and attenuated tumor cell proliferation. During osteoclastogenesis, changes in DNA methylation occurred in numerous genes, implicating important roles for DNA methylation in osteoclastogenesis. In the present study, we found that decitabine inhibited osteoclastogenesis. The inhibitory effect could be at least partially attributed to reduced expression of multiple osteoclast specific genes including RANK by decitabine. Moreover, decitabine inhibited activity of NF-κB, AP-1 and extracellular signal-regulated kinase (ERK), but not PI3K/Akt pathway. In vivo, using ovariectomized mouse as a model, we observed that decitabine reduced the osteoclast activity and bone loss. In conclusion, our findings demonstrated that decitabine was an inhibitor of osteoclastogenesis by repression of osteoclast specific transcription program including the RANK, NF-κB and AP-1 pathways. DNA methylation might be indispensable for osteoclastogenesis. The use of decitabine could represent a novel strategy in treatment of diseases associated with increased osteoclast activity.
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Hanfeng
authors: H
authors: Guan
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Baoguo
authors: B
authors: Mi
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Yong
authors: Y
authors: Li
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Wei
authors: W
authors: Wu
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Peng
authors: P
authors: Tan
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Zhong
authors: Z
authors: Fang
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Jing
authors: J
authors: Li
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Yong
authors: Y
authors: Zhang
authors: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: lifengmd@hust.edu.cn.
authors: Feng
authors: F
authors: Li
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D005260:Female; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D053245:RANK Ligand; D018808:Transcription Factor AP-1; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine
keywords: DNA methylation; Decitabine; NF-κB; Osteoclast; RANK