title: ARTD1 regulates osteoclastogenesis and bone homeostasis by dampening NF-κB-dependent transcription of IL-1β.
abstract: While ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly PARP1) and its enzymatic activity have been shown to be important for reprogramming and differentiation of cells, such as during adipogenesis, their role and mechanism in regulating osteoclastogenesis and bone homeostasis are largely unknown. Here, in cell culture-based RANKL-induced osteoclastogenesis models, we show that silencing of ARTD1 or inhibition of its enzymatic activity enhances osteoclast differentiation and function. As a consequence of ARTD1 silencing or inhibition, the recruitment of p65/RelA to the IL-1β promoter, which is associated with transcriptionally active histone marks, IL-1β expression and inflammasome-dependent secretion of IL-1β are enhanced. This subsequently promotes sustained induction of the transcription factor Nfatc1/A and osteoclastogenesis in an autocrine manner via the IL-1 receptor. In vivo, Artd1-deficient mice display significantly decreased bone mass as a consequence of increased osteoclast differentiation. Accordingly, the expression of osteoclast markers is enhanced in mutant compared to wild-type mice. Together, these results indicate that ARTD1 controls osteoclast development and bone remodelling via its enzymatic activity by modulating the epigenetic marks surrounding the IL-1β promoter and expression of IL-1β and subsequently also Nfatc1/A.
authors.affiliation: Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.|Department of Environmental Pollution Biophysics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Robaszkiewicz
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8301, St. Louis, MO 63110.
authors.forename: Chao
authors.initials: C
authors.lastname: Qu
authors.affiliation: Department of Environmental Pollution Biophysics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Wisnik
authors.affiliation: Department of Molecular Biology, Medical University of Lodz, Narutowicza 60, 90-136 Lodz, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Ploszaj
authors.affiliation: Competence Centre for Applied Biotechnology and Molecular Medicine, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Ali
authors.initials: A
authors.lastname: Mirsaidi
authors.affiliation: Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.|Life Science Zurich Graduate School, Molecular Life Science Program, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Kunze
authors.affiliation: Competence Centre for Applied Biotechnology and Molecular Medicine, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Richards
authors.affiliation: Division of Trauma Surgery, Center for Clinical Research, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cinelli
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8301, St. Louis, MO 63110.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
authors.affiliation: Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.|Competence Centre for Applied Biotechnology and Molecular Medicine, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001665:Binding Sites; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006706:Homeostasis; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D000071137:Poly (ADP-Ribose) Polymerase-1; D004250:DNA Topoisomerases, Type II