RRC ID 44491
Author Kanzaki H, Shinohara F, Kajiya M, Kodama T.
Title The Keap1/Nrf2 protein axis plays a role in osteoclast differentiation by regulating intracellular reactive oxygen species signaling.
Journal J Biol Chem
Abstract Reactive oxygen species (ROS) act as intracellular signaling molecules in the regulation of receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclast differentiation, but they also have cytotoxic effects that include peroxidation of lipids and oxidative damage to proteins and DNA. Cellular protective mechanisms against oxidative stress include transcriptional control of cytoprotective enzymes by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). This study investigated the relationship between Nrf2 and osteoclastogenesis. Stimulation of osteoclast precursors (mouse primary peritoneal macrophages and RAW 264.7 cells) with RANKL resulted in the up-regulation of kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2. It also decreased the Nrf2/Keap1 ratio, and it down-regulated cytoprotective enzymes (heme oxygenase-1, γ-glutamylcysteine synthetase, and glucose-6-phosphate dehydrogenase). Nrf2 overexpression up-regulated the expression of cytoprotective enzymes, decreased ROS levels, decreased the number of tartrate-resistant acid phosphatase-positive multinucleated cells, reduced marker genes for osteoclast differentiation, and attenuated bone destruction in both in vitro and in vivo models. Overexpression of Keap1 or RNAi knockdown of Nrf2 exerted the opposite actions. In addition, in vivo local Nrf2 overexpression attenuated lipopolysaccharide-mediated RANKL-dependent cranial bone destruction in vivo. This is the first study to show that the Keap1/Nrf2 axis regulates RANKL-dependent osteoclastogenesis through modulation of intracellular ROS signaling via expression of cytoprotective enzymes. This raises the exciting possibility that the Keap1-Nrf2 axis may be a therapeutic target for the treatment of bone destructive disease.
Volume 288(32)
Pages 23009-20
Published 2013-8-9
DOI 10.1074/jbc.M113.478545
PII S0021-9258(20)45328-1
PMID 23801334
PMC PMC3743476
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Animals Cell Differentiation* Cell Line Cytoskeletal Proteins / genetics Cytoskeletal Proteins / metabolism* Gene Expression Regulation / drug effects Gene Expression Regulation / genetics Kelch-Like ECH-Associated Protein 1 Lipopolysaccharides / pharmacology Macrophages, Peritoneal / metabolism* Macrophages, Peritoneal / pathology Mice NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism* Osteoclasts / metabolism* Osteoclasts / pathology Osteolysis / genetics Osteolysis / metabolism Osteolysis / pathology RANK Ligand / biosynthesis Reactive Oxygen Species / metabolism* Signal Transduction*
IF 4.238
Times Cited 66
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells RAW 264(RCB0535)