title: Defective entry into mitosis 1 (Dim1) negatively regulates osteoclastogenesis by inhibiting the expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1).
abstract: Bone remodeling is a continuous process of osteoblastic bone formation and osteoclastic bone resorption to maintain normal bone mass. NFATc1 is the master regulator of osteoclastogensis and transcriptionally activated by c-Fos and NF-κB in response to receptor activator of NF-κB ligand (RANKL) treatment. Defective entry into mitosis 1 (Dim1) is a nuclear protein that is implicated in pre-mRNA splicing and cell cycle progression, but the possible role of Dim1 in regulating other cellular processes remains unknown. Here, we demonstrate that Dim1 attenuates RANKL-induced osteoclastogenesis by targeting NFATc1 signaling pathway. Expression levels of Dim1 and NFATc1 are significantly increased during the formation of multinucleated osteoclasts. RNAi-mediated knockdown of Dim1 markedly enhances the expression of NFATc1 and its target genes, leading to the increase of RANKL-induced osteoclastogenesis in bone marrow-derived macrophages. Conversely, ectopic expression of Dim1 decreases RANKL-induced osteoclast differentiation by silencing NFATc1 and its target genes, further linking Dim1 to the dynamic regulation of osteoclastogenesis. Consistent with this notion, ChIP and interaction studies show that Dim1 directly associates with c-Fos and prevents c-Fos from binding to the NFATc1 promoter, resulting in targeted inactivation of the NFATc1 gene. Therefore, our studies reveal an unrecognized role for Dim1 as a master modulator of osteoclast differentiation, as well as the molecular mechanism underlying its repressive action toward osteoclastogensis.
authors.affiliation: From the Department of Stem Cell Biology and Regenerative Medicine, Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, Neuroscience Program, College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California 90089.
authors.forename: Daniel
authors.initials: D
authors.lastname: An
authors.affiliation: the Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, and kyunghki@usc.edu.
authors.forename: Kyunghwan
authors.initials: K
authors.lastname: Kim
authors.affiliation: From the Department of Stem Cell Biology and Regenerative Medicine, Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, wangelu@usc.edu.
authors.forename: Wange
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D015536:Down-Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000502:physiology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; C000594658:Dim1 protein, mouse; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse
keywords: Chromatin; Dim1; FBJ Murine Osteosarcoma Viral Oncogene Homolog (FOS); Gene Expression; NFAT Transcription Factor; NFATc1; Osteoclast; Osteoclastogenesis; RANKL; c-Fos