NRROS Negatively Regulates Osteoclast Differentiation by Inhibiting RANKL-Mediated NF-κB and Reactive Oxygen Species Pathways

Kim, Jung Ha; Kim, Kabsun; Kim, In-Young; Seong, Semun; Kim, Nacksung

doi:10.14348/molcells.2015.0177

Cited by 24 publications

(13 citation statements)

References 19 publications

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“…In previous researches, LRRC33 is known as the Negative Regulator of Reactive Oxygen Species (NRROS), and its function is down-regulating of reactive oxygen species during host defense and autoimmunity on gene knock-out mice [25]. And a following research by another group indicates that LRRC33 regulates osteoclast differentiation [26]. In our previous research, it is indicated that the LRRC33 homologous protein, GARP (LRRC32), binds to pro-TGF-β1 and exert TGF-β1 regulating functions [17].…”

Section: Discussionmentioning

confidence: 99%

LRRC33 is a novel binding and potential regulating protein of TGF-β1 function in human acute myeloid leukemia cells

Yan

Chapuy

et al. 2019

PLoS ONE

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Transforming growth factor‑β1 (TGF-β1) is a versatile cytokine. It has context-dependent pro- and anti-cell proliferation functions. Activation of latent TGF-β1 requires release of the growth factor from pro-complexes and is regulated through TGF-β binding proteins. Two types of TGF-β binding partners, latent TGF-β-binding proteins (LTBPs) and leucine-rich-repeat-containing protein 32 (LRRC32), have been identified and their expression are cell specific. TGF-β1 also plays important roles in acute myeloid leukemia (AML) cells. However, the expression of LTBPs and LRRC32 are lacking in myeloid lineage cells and the binding protein of TGF-β1 in these cells are unknown. Here we show that a novel leucine-rich-repeat-containing protein family member, LRRC33, with high mRNA level in AML cells, to be the binding and regulating protein of TGF-β1 in AML cells. Using two representative cell lines MV4-11 and AML193, we demonstrate that the protein expression of LRRC33 and TGF-β1 are correlated. LRRC33 co-localizes and forms complex with latent TGF-β1 protein on the cell surface and intracellularly in these cells. Similar as in other cell types, the activation of TGF-β1 in MV4-11 and AML193 cells are also integrin dependent. We anticipate our study to be a starting point of more comprehensive research on LRRC33 as novel TGF-β regulating protein and potential non-genomic based drug target for AML and other myeloid malignancy.

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Section: Discussionmentioning

confidence: 99%

LRRC33 is a novel binding and potential regulating protein of TGF-β1 function in human acute myeloid leukemia cells

Yan

Chapuy

et al. 2019

PLoS ONE

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“…Recently, it has been reported that cellular NOX2 level is modulated by a negative regulator of ROS (NRROS) by degrading NOX2 dependent ER associated pathway [61]. NRROS increased during OC differentiation and suppressed NOX2 expression, which subsequently masked RANKL-induced OC differentiation [61]. These reports suggest that NOX2 expression and NOX2 derived ROS are closely controlled by negative regulatory frameworks.…”

Section: Ros In Oc Differentiation and Activitymentioning

confidence: 99%

Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases

Agidigbi

Kim

2019

IJMS

323

230

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Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction–oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O2−) and hydrogen peroxide (H2O2), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases.

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“…More recently, Kim et al . reported that NRROS is increased during osteoclast differentiation and represses Nox1 and Nox2 expression, thereby attenuating RANKL-induced osteoclast differentiation15. These findings suggest that Nox2 expression and Nox2-derived ROS are tightly controlled by negative regulatory networks.…”

mentioning

confidence: 77%

NADPH oxidase gp91phox contributes to RANKL-induced osteoclast differentiation by upregulating NFATc1

Kang

Kim

2016

Sci Rep

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Bone-marrow derived monocyte-macrophages (BMMs) differentiate into osteoclasts by M-CSF along subsequent RANKL stimulation possibly in collaboration with many other unknown cytokines released by pre- or mature osteoblasts. The differentiation process requires receptor activator of nuclear factor kappa-B ligand (RANKL)/RANK signaling and reactive oxygen species (ROS) such as superoxide anion (O2•−). Gp91phox, a plasma membrane subunit of NADPH oxidase (Nox), is constitutively expressed in BMMs and plays a major role in superoxide anion production. In this study, we found that mice deficient in gp91phox (gp91phox−/−) showed defects in osteoclast differentiation. Femurs of these mice produced osteoclasts at about 70% of the levels seen in femurs from wild-type mice, and accordingly exhibited excessive bone density. This abnormal bone growth in the femurs of gp91phox−/− mice resulted from impaired osteoclast differentiation. In addition, gp91phox−/− mice were defective for RANKL-induced expression of nuclear factor of activated T cells c1 (NFATc1). However, H2O2 treatment compensated for gp91phox deficiency in BMMs, almost completely rescuing osteoclast differentiation. Treating wild-type BMMs with antioxidants and superoxide inhibitors resulted in a differentiation defect resembling the phenotype of gp91phox−/− BMMs. Therefore, our results demonstrate that gp91phox-derived superoxide is important for promoting efficient osteoclast differentiation by inducing NFATc1 as a downstream signaling mediator of RANK.

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NRROS Negatively Regulates Osteoclast Differentiation by Inhibiting RANKL-Mediated NF-κB and Reactive Oxygen Species Pathways

Cited by 24 publications

References 19 publications

LRRC33 is a novel binding and potential regulating protein of TGF-β1 function in human acute myeloid leukemia cells

LRRC33 is a novel binding and potential regulating protein of TGF-β1 function in human acute myeloid leukemia cells

Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases

NADPH oxidase gp91phox contributes to RANKL-induced osteoclast differentiation by upregulating NFATc1

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