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Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation.
Free Radic Biol Med. 2013 Dec; 65:789-799.FR

Abstract

Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of a variety of antioxidant and detoxification genes through an antioxidant-response element. Nrf2 has been shown to protect several types of cells against the acute and chronic injury that accompanies oxidative stress, but its role in osteoclasts remains unclear. In this study, we investigated the role of Nrf2 in osteoclast (OC) differentiation, a process in which reactive oxygen species (ROS) are generated and then participate, using Nrf2-knockout mice. Receptor activator of nuclear factor κB ligand (RANKL)-induced OC differentiation, actin ring formation, and osteoclastic bone resorption were substantially promoted in Nrf2-deficient OC precursor cells compared to wild-type cells. Under both unstimulated and RANKL-stimulated conditions, Nrf2 loss led to an increase in the intracellular ROS level and the oxidized-to-reduced glutathione ratio and a defect in the production of numerous antioxidant enzymes and glutathione. Moreover, pretreatment with N-acetylcysteine or diphenyleneiodonium significantly reduced the OC differentiation and decreased the intracellular ROS level in both Nrf2-deficient and wild-type cells. Pretreatment with sulforaphane and curcumin also inhibited the OC differentiation by activating Nrf2 in part. Nrf2 deficiency promoted the RANKL-induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; the induction of c-Fos; and the consequent induction of nuclear factor of activated T cells, cytoplasmic 1, a pivotal determinant of OC differentiation. Our results suggest that Nrf2 probably inhibits RANKL-induced OC differentiation by regulating the cellular redox status by controlling the expression of oxidative response genes, findings that might form the basis of a new strategy for treating inflammatory bone diseases.

Authors+Show Affiliations

Department of Life Science and Research Center for Cellular Homeostasis, Ewha Woman's University, Seoul 120-750, Korea.Department of Life Science and Research Center for Cellular Homeostasis, Ewha Woman's University, Seoul 120-750, Korea.Department of Life Science and Research Center for Cellular Homeostasis, Ewha Woman's University, Seoul 120-750, Korea.Department of Life Science and Research Center for Cellular Homeostasis, Ewha Woman's University, Seoul 120-750, Korea. Electronic address: jeongw@ewha.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23954472

Citation

Hyeon, Seungha, et al. "Nrf2 Deficiency Induces Oxidative Stress and Promotes RANKL-induced Osteoclast Differentiation." Free Radical Biology & Medicine, vol. 65, 2013, pp. 789-799.
Hyeon S, Lee H, Yang Y, et al. Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radic Biol Med. 2013;65:789-799.
Hyeon, S., Lee, H., Yang, Y., & Jeong, W. (2013). Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radical Biology & Medicine, 65, 789-799. https://doi.org/10.1016/j.freeradbiomed.2013.08.005
Hyeon S, et al. Nrf2 Deficiency Induces Oxidative Stress and Promotes RANKL-induced Osteoclast Differentiation. Free Radic Biol Med. 2013;65:789-799. PubMed PMID: 23954472.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. AU - Hyeon,Seungha, AU - Lee,Hyojung, AU - Yang,Yoohee, AU - Jeong,Woojin, Y1 - 2013/08/14/ PY - 2013/02/05/received PY - 2013/08/01/revised PY - 2013/08/06/accepted PY - 2013/8/20/entrez PY - 2013/8/21/pubmed PY - 2015/7/15/medline KW - AP-1 KW - ARE KW - BMM KW - DPI KW - ERK KW - FBS KW - Free radicals KW - GSH KW - GSSG KW - JNK KW - Keap1 KW - Kelch-like ECH-associated protein 1 KW - M-CSF KW - MAPK KW - MAPK phosphatase KW - MEM KW - MKP KW - Mitogen-activated protein kinases KW - N-acetylcysteine KW - NAC KW - NAD(P)H:quinone oxidoreductase 1 KW - NADPH KW - NADPH oxidase KW - NF-κB KW - NFATc1 KW - NQO1 KW - Nox KW - Nrf2 KW - OC KW - OC differentiation KW - PBS KW - Prx KW - RANKL KW - ROS KW - Reactive oxygen species KW - Redox regulation KW - SOD KW - Srx KW - TNF KW - TNF receptor-associated factor KW - TRAF KW - TRAP KW - TRAP(+) MNC KW - TRAP-positive multinucleated cell KW - Trx KW - Trx reductase KW - TrxR KW - activator protein-1 KW - antioxidant response element KW - bone marrow-derived macrophage KW - c-Jun N-terminal kinase KW - diphenyleneiodonium KW - extracellular signal-regulated kinase KW - fetal bovine serum KW - glutathione KW - macrophage colony-stimulating factor KW - minimal essential medium KW - mitogen-activated protein kinase KW - nicotinamide adenine dinucleotide phosphate KW - nuclear factor of activated T cells, cytoplasmic 1 KW - nuclear factor-erythroid 2-related factor 2 KW - nuclear factor-κB KW - osteoclast KW - oxidized GSH KW - peroxiredoxin KW - phosphate-buffered saline KW - reactive oxygen species KW - receptor activator of NF-κB ligand KW - sulfiredoxin KW - superoxide dismutase KW - tartrate-resistant acid phosphatase KW - thioredoxin KW - tumor necrosis factor SP - 789 EP - 799 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 65 N2 - Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of a variety of antioxidant and detoxification genes through an antioxidant-response element. Nrf2 has been shown to protect several types of cells against the acute and chronic injury that accompanies oxidative stress, but its role in osteoclasts remains unclear. In this study, we investigated the role of Nrf2 in osteoclast (OC) differentiation, a process in which reactive oxygen species (ROS) are generated and then participate, using Nrf2-knockout mice. Receptor activator of nuclear factor κB ligand (RANKL)-induced OC differentiation, actin ring formation, and osteoclastic bone resorption were substantially promoted in Nrf2-deficient OC precursor cells compared to wild-type cells. Under both unstimulated and RANKL-stimulated conditions, Nrf2 loss led to an increase in the intracellular ROS level and the oxidized-to-reduced glutathione ratio and a defect in the production of numerous antioxidant enzymes and glutathione. Moreover, pretreatment with N-acetylcysteine or diphenyleneiodonium significantly reduced the OC differentiation and decreased the intracellular ROS level in both Nrf2-deficient and wild-type cells. Pretreatment with sulforaphane and curcumin also inhibited the OC differentiation by activating Nrf2 in part. Nrf2 deficiency promoted the RANKL-induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; the induction of c-Fos; and the consequent induction of nuclear factor of activated T cells, cytoplasmic 1, a pivotal determinant of OC differentiation. Our results suggest that Nrf2 probably inhibits RANKL-induced OC differentiation by regulating the cellular redox status by controlling the expression of oxidative response genes, findings that might form the basis of a new strategy for treating inflammatory bone diseases. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/23954472/Nrf2_deficiency_induces_oxidative_stress_and_promotes_RANKL_induced_osteoclast_differentiation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(13)00406-1 DB - PRIME DP - Unbound Medicine ER -