PMID- 32967239 OWN - NLM STAT- MEDLINE DCOM- 20210324 LR - 20221205 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 9 IP - 9 DP - 2020 Sep 21 TI - NRF2 Is an Upstream Regulator of MYC-Mediated Osteoclastogenesis and Pathological Bone Erosion. LID - 10.3390/cells9092133 [doi] LID - 2133 AB - Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating drug side effects and enhancing cell specificity. Recently, we demonstrated the crucial role of MYC and its downstream effectors in driving osteoclast differentiation. Despite these advances, upstream regulators of MYC have not been well defined. In this study, we identify nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor known to regulate the expression of phase II antioxidant enzymes, as a novel upstream regulator of MYC. NRF2 negatively regulates receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis through the ERK and p38 signaling-mediated suppression of MYC transcription. Furthermore, the ablation of MYC in osteoclasts reverses the enhanced osteoclast differentiation and activity in NRF2 deficiency in vivo and in vitro in addition to protecting NRF2-deficient mice from pathological bone loss in a murine model of inflammatory arthritis. Our findings indicate that this novel NRF2-MYC axis could be instrumental for the fine-tuning of osteoclast formation and provides additional ways in which osteoclasts could be therapeutically targeted to prevent pathological bone erosion. FAU - Park, Peter Sang Uk AU - Park PSU AUID- ORCID: 0000-0002-2223-7151 AD - Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA. FAU - Mun, Se Hwan AU - Mun SH AD - Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA. FAU - Zeng, Steven L AU - Zeng SL AD - Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA. FAU - Kim, Haemin AU - Kim H AD - Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA. FAU - Bae, Seyeon AU - Bae S AD - Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA. FAU - Park-Min, Kyung-Hyun AU - Park-Min KH AD - Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA. AD - BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA. LA - eng GR - R01 AR069562/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20200921 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole) RN - 0 (Imidazoles) RN - 0 (Myc protein, mouse) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0 (RANK Ligand) RN - 0 (RNA, Small Interfering) RN - 0 (Tnfsf11 protein, mouse) RN - 6SMK8R7TGJ (Oleanolic Acid) RN - EC 2.7.11.24 (Mapk1 protein, mouse) RN - EC 2.7.11.24 (Mapk3 protein, mouse) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Arthritis, Experimental/*genetics/metabolism/pathology MH - Bone and Bones/drug effects/*metabolism/pathology MH - Cell Differentiation/drug effects MH - Gene Expression Regulation MH - Imidazoles/pharmacology MH - Male MH - Mice MH - Mice, Knockout MH - Mitogen-Activated Protein Kinase 1/genetics/metabolism MH - Mitogen-Activated Protein Kinase 3/genetics/metabolism MH - NF-E2-Related Factor 2/agonists/antagonists & inhibitors/*genetics/metabolism MH - Oleanolic Acid/analogs & derivatives/pharmacology MH - Osteoclasts/cytology/*metabolism MH - Osteogenesis/*genetics MH - Proto-Oncogene Proteins c-myc/*genetics/metabolism MH - RANK Ligand/genetics/metabolism MH - RAW 264.7 Cells MH - RNA, Small Interfering/genetics/metabolism MH - Signal Transduction MH - p38 Mitogen-Activated Protein Kinases/genetics/metabolism PMC - PMC7564846 OTO - NOTNLM OT - MYC OT - NRF2 OT - RANKL signaling OT - osteoclasts COIS- The authors declare no conflict of interest. EDAT- 2020/09/25 06:00 MHDA- 2021/03/25 06:00 PMCR- 2020/09/01 CRDT- 2020/09/24 01:01 PHST- 2020/07/06 00:00 [received] PHST- 2020/09/07 00:00 [revised] PHST- 2020/09/17 00:00 [accepted] PHST- 2020/09/24 01:01 [entrez] PHST- 2020/09/25 06:00 [pubmed] PHST- 2021/03/25 06:00 [medline] PHST- 2020/09/01 00:00 [pmc-release] AID - cells9092133 [pii] AID - cells-09-02133 [pii] AID - 10.3390/cells9092133 [doi] PST - epublish SO - Cells. 2020 Sep 21;9(9):2133. doi: 10.3390/cells9092133.