A New Superoxide-generating Oxidase in Murine Osteoclasts

Yang, Stephen C.; Madyastha, Prema; Bingel, Sarah A.; Ries, William L.; Key, L. Lyndon

doi:10.1074/jbc.m001004200

Cited by 191 publications

(157 citation statements)

References 28 publications

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“…The mechanism by which superoxide participates in bone resorption is not clear, but may involve direct oxidation of calcium binding sites and/or acidification of the local environment near osteoclasts. Nox4 in osteoclasts may be the source of the ROS in bone [201].…”

Section: Nox Enzymes In Muscle Cartilage and Bone A Bone Resorptionmentioning

confidence: 99%

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

578

454

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Section: Nox Enzymes In Muscle Cartilage and Bone A Bone Resorptionmentioning

confidence: 99%

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

578

454

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“…Previous reports suggest that ROS, such as hydrogen peroxide and superoxide, enhance bone resorption 8,9 and that the partial depletion of glutathione brought on by treatment with a small amount of L-buthionine-(S,R)-sulfoximine (BSO, 10 mM), a specific inhibitor of g-GCS, stimulates RANKL-induced OC differentiation. 17 These results suggest that the severe depletion and adequate repletion of glutathione at the period of RANKL-induced glutathione reduction could have an effect on OC differentiation.…”

Section: Effects Of An Oxidizing or Reducing Cellular Redox Status Onmentioning

confidence: 99%

“…Bar, 25 mm OC formation and bone resorption. 8,9,11,17 Overexpression of catalase 10 and treatment with DPI, 11 a specific NADPH oxidase inhibitor, have indeed been shown to decrease superoxide production in OCs and block OC formation and bone resorption. In addition, it has been reported that a small amount of H 2 O 2 (1 mM) and a partial depletion of the intracellular glutathione pool by BSO (10 mM) enhance RANKL-induced OC differentiation via NF-kB activation.…”

Section: Inhibitory Effect Of Combined Rankl and Bso On Cell Growthmentioning

confidence: 99%

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Regulation of osteoclast differentiation by the redox-dependent modulation of nuclear import of transcription factors

Kim

et al. 2005

Cell Death Differ

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This study sought to characterize the reduced glutathione (GSH)/oxidized GSSG ratio during osteoclast differentiation and determine whether changes in the intracellular redox status regulate its differentiation through a RANKL-dependent signaling pathway. A progressive decrease of the GSH/ GSSG ratio was observed during osteoclast differentiation, and the phenomenon was dependent on a decrease in total glutathione via downregulation of expression of the cglutamylcysteinyl synthetase modifier gene. Glutathione depletion by L-buthionine-(S,R)-sulfoximine (BSO) was found to inhibit osteoclastogenesis by blocking nuclear import of NF-jB and AP-1 in RANKL-propagated signaling and bone pit formation by increasing BSO concentrations in mature osteoclasts. Furthermore, intraperitoneal injection of BSO in mice resulted in an increase in bone density and a decrease of the number of osteoclasts in bone. Conversely, glutathione repletion with either N-acetylcysteine or GSH enhanced osteoclastogenesis. These findings indicate that redox status decreases during osteoclast differentiation and that this modification directly regulates RANKL-induced osteoclastogenesis.

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“…The Nox family of NAD(P)H oxidases has recently been described (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). These enzymes are structural homologs of gp91 phox (a.k.a.…”

mentioning

confidence: 99%

Nox3 Regulation by NOXO1, p47 , and p67

Cheng

Ritsick

Lambeth

2004

Journal of Biological Chemistry

141

118

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gp91 phox (Nox2), the catalytic subunit of the superoxide-generating respiratory burst oxidase, is regulated by subunits p47 phox and p67 phox . Nox1, a homolog of gp91 phox , is regulated by NOXO1 and NOXA1, homologs of p47 phox and p67 phox , respectively. For both Nox1 and gp91 phox , an organizer protein (NOXO1 or p47 phox ) cooperates with an activator protein (NOXA1 or p67 phox ) to regulate the catalytic subunit. Herein, we investigate the subunit regulation of Nox3 compared with that of other Nox enzymes. Nox3, like gp91 phox , was activated by p47 phox plus p67 phox . Whereas gp91 phox activity required the protein kinase C activator phorbol myristate acetate (PMA), Nox3 activity was already high without PMA, but was further stimulated ϳ30% by PMA. gp91 phox was also activated by NOXO1/NOXA1 and required PMA for high activity. gp91 phox regulation required an intact activation domain in the activator protein, as neither p67 phox (V204A) nor NOXA1(V205A) were effective. In contrast, p67 phox (V204A) was effective (along with p47 phox ) in activating Nox3. Unexpectedly, Nox3 was strongly activated by NOXO1 in the absence of NOXA1 or p67 phox . Nox3 activity was regulated by PMA only when p47 phox but not NOXO1 was present, consistent with the phosphorylation-regulated autoinhibitory region in p47 phox but not in NOXO1. Deletion of the autoinhibitory region from p47 phox rendered this subunit highly active in the absence of PMA toward both gp91 phox and Nox3, and high activity required an activator subunit. The unique regulation of Nox3 supports a model in which multiple interactions with regulatory subunits stabilize an active conformation of the catalytic subunit.The Nox family of NAD(P)H oxidases has recently been described (1-10). These enzymes are structural homologs of gp91 phox (a.k.a. Nox2), the catalytic subunit of the phagocyte NADPH oxidase, and are distributed in a variety of non-phagocytic tissues such as colon, kidney, vascular smooth muscle, and brain. Reactive oxygen species generated by these novel enzymes are proposed to function in signal transduction related to cell growth and cancer (1,(11)(12)(13)(14)(15)(16)(17), angiogenesis (18), and in innate immunity (15), e.g. in barrier cells such as epithelium. In addition, reactive oxygen species from these enzymes are proposed to be causally linked to pathological states including atherosclerosis (19), cancer (11,15,20,21), and diabetes (22).The human Nox enzymes are encoded by at least 7 genes. NOX1, NOX3, and NOX4 encode proteins that are similar in size and domain structure to gp91 phox . These consist of a Cterminal flavoprotein domain containing both an FAD-binding site and an NADPH-binding site, and an N-terminal membrane-associated hydrophobic domain consisting of 6 transmembrane ␣ helices that provide binding sites for 2 hemes (3). Nox5 consists of these same domains along with an N-terminal calcium-binding domain (9); this enzyme is dormant when expressed in cells, but is activated by calcium. Duox1 and Duox2 build upon the Nox5 str...

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A New Superoxide-generating Oxidase in Murine Osteoclasts

Cited by 191 publications

References 28 publications

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Regulation of osteoclast differentiation by the redox-dependent modulation of nuclear import of transcription factors

Nox3 Regulation by NOXO1, p47 , and p67

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