Role of mitochondrial reactive oxygen species in osteoclast differentiation.
Previously we showed that hypoxia-induced mitochondrial respiratory stress in RAW 264.7 macrophages and other cells caused activation of retrograde signaling (also known as mitochondrial respiratory stress signaling) and the appearance of tartrate-resistant acid phosphatase (TRAP)-positive cells. In the present study, we used N-acetyl cysteine and ascorbate (general antioxidants) and MitoQ, a mitochondria-specific antioxidant, to investigate the role of intracellular reactive oxygen species (ROS) in osteoclast differentiation. Our results show that hypoxia-mediated mitochondrial dysfunction, as tested by disruption of mitochondrial transmembrane potential, was suppressed by MitoQ as well as by the other antioxidants. These agents also suppressed the activation of mitochondrial retrograde signaling. Interestingly, in terms of molar concentrations, MitoQ was more than 1000-fold more effective than general antioxidants in suppressing the receptor activator of nuclear factor-B ligand-induced differentiation of RAW 264.7 cells into multinucleated and TRAP-positive osteoclasts. We propose that mitochondrial function and intramitochondrial ROS play important roles in osteoclastogenesis.
Srinivasan
Satish
S
Department of Animal Biology, University of Pennsylvania, Philadelphia, PA, USA.
Koenigstein
Alexander
A
Joseph
Joy
J
Sun
Li
L
Kalyanaraman
B
B
Zaidi
Mone
M
Avadhani
Narayan G
NG
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D007527:Isoenzymes / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D000071681:Tartrate-Resistant Acid Phosphatase; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
D000975:Antioxidants; D007527:Isoenzymes; D016328:NF-kappa B; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C429014:mitoquinone; D019703:Calcineurin; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
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