scholarly journals IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss

2005 ◽  
Vol 201 (10) ◽  
pp. 1677-1687 ◽  
Author(s):  
Maria Grazia Ruocco ◽  
Shin Maeda ◽  
Jin Mo Park ◽  
Toby Lawrence ◽  
Li-Chung Hsu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Osteoclast Survival

Transcription factor, nuclear factor κB (NF-κB), is required for osteoclast formation in vivo and mice lacking both of the NF-κB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IκB kinase (IKK) complex that mediate NF-κB activation, IKKα and IKKβ, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKβ subunit as a transducer of signals from receptor activator of NF-κB (RANK) to NF-κB. Although IKKα is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKβ is required for osteoclastogenesis in vitro and in vivo. IKKβ also protects osteoclasts and their progenitors from tumor necrosis factor α–induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.

scholarly journals The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis

1999 ◽  
Vol 189 (11) ◽  
pp. 1839-1845 ◽  
Author(s):  
Zhi-Wei Li ◽  
Wenming Chu ◽  
Yinling Hu ◽  
Mireille Delhase ◽  
Tom Deerinck ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Nuclear Factor ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

scholarly journals Fermented Oyster Extract Prevents Ovariectomy-Induced Bone Loss and Suppresses Osteoclastogenesis

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1392 ◽  
Author(s):  
Hye Jung Ihn ◽  
Ju Ang Kim ◽  
Soomin Lim ◽  
Sang-Hyeon Nam ◽  
So Hyeon Hwang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Type I Collagen ◽  
Therapeutic Option ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Type I ◽  
Bioactive Substances

There is growing interest in bioactive substances from marine organisms for their potential use against diverse human diseases. Osteoporosis is a skeletal disorder associated with bone loss primarily occurring through enhanced osteoclast differentiation and resorption. Recently, we reported the anti-osteoclastogenic activity of fermented Pacific oyster (Crassostrea gigas) extract (FO) in vitro. The present study focused on investigating the anti-osteoporotic efficacy of FO in bone loss prevention in an experimental animal model of osteoporosis and elucidating the mechanism underlying its effects. Oral administration of FO significantly decreased ovariectomy-induced osteoclast formation and prevented bone loss, with reduced serum levels of bone turnover biomarkers including osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus (CTX). FO significantly suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts and attenuated the induction of osteoclast-specific genes required for osteoclastogenesis and bone resorption. Furthermore, FO inhibited RANKL-mediated IκBα and p65 phosphorylation in BMMs. Taken together, these results demonstrate that FO effectively suppresses osteoclastogenesis in vivo and in vitro, and that FO can be considered as a potential therapeutic option for the treatment of osteoporosis and osteoclast-mediated skeletal diseases.

Small molecule inhibitors of IκB kinase signaling inhibit osteoclast formation in vitro and prevent ovariectomy‐induced bone loss in vivo

2010 ◽  
Vol 24 (11) ◽  
pp. 4545-4555 ◽  
Author(s):  
Aymen I. Idris ◽  
Maala Krishnan ◽  
Petra Simic ◽  
Euphemie Landao‐Bassonga ◽  
Patrick Mollat ◽  
...  
Keyword(s):  
Bone Loss ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Osteoclast Formation ◽  
Kinase Signaling ◽  
Iκb Kinase ◽  
Inhibit Osteoclast Formation

scholarly journals Scutellarein inhibits RANKL‐induced osteoclast formation in vitro and prevents LPS‐induced bone loss in vivo

2018 ◽  
Vol 234 (7) ◽  
pp. 11951-11959 ◽  
Author(s):  
Fangsheng Fu ◽  
Siyuan Shao ◽  
Ziyi Wang ◽  
Fangming Song ◽  
Xixi Lin ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Formation

scholarly journals MEKK1 activates both IκB kinase α and IκB kinase β

1998 ◽  
Vol 95 (16) ◽  
pp. 9319-9324 ◽  
Author(s):  
Frank S. Lee ◽  
Robert T. Peters ◽  
Luan C. Dang ◽  
Tom Maniatis
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Mitogen Activated Protein Kinase ◽  
Site Specific ◽  
Iκb Kinase ◽  
Mitogen Activated Protein ◽  
Bona Fide ◽  
Factor Α

A critical step in the signal-induced activation of the transcription factor NF-κB is the site-specific phosphorylation of its inhibitor, IκB, that targets the latter for degradation by the ubiquitin–proteasome pathway. We have previously shown that mitogen-activated protein kinase/ERK kinase kinase 1 (MEKK1) can induce both this site-specific phosphorylation of IκBα at Ser-32 and Ser-36 in vivo and the activity of a high molecular weight IκB kinase complex in vitro. Subsequently, others have identified two proteins, IκB kinase α (IKK-α) and IκB kinase β (IKK-β), that are present in a tumor necrosis factor α-inducible, high molecular weight IκB kinase complex. These kinases are believed to directly phosphorylate IκB based on the examination of the kinase activities of IKK immunoprecipitates, but more rigorous proof of this has yet to be demonstrated. We show herein that recombinant IKK-α and IKK-β can, in fact, directly phosphorylate IκBα at Ser-32 and Ser-36, as well as homologous residues in IκBβ in vitro, and thus are bona fide IκB kinases. We also show that MEKK1 can induce the activation of both IKK-α and IKK-β in vivo. Finally, we show that IKK-α is present in the MEKK1-inducible, high molecular weight IκB kinase complex and treatment of this complex with MEKK1 induces phosphorylation of IKK-α in vitro. We conclude that IKK-α and IKK-β can mediate the NF-κB-inducing activity of MEKK1.

scholarly journals Suppression Effect of Astaxanthin on Osteoclast Formation In Vitro and Bone Loss In Vivo

2018 ◽  
Vol 19 (3) ◽  
pp. 912 ◽  
Author(s):  
Yun-Ho Hwang ◽  
Kwang-Jin Kim ◽  
Su-Jin Kim ◽  
Seul-Ki Mun ◽  
Seong-Gyeol Hong ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Formation ◽  
Suppression Effect

Regulation of granulocyte apoptosis by NF-κB

2004 ◽  
Vol 32 (3) ◽  
pp. 465-467 ◽  
Author(s):  
C. Ward ◽  
A. Walker ◽  
I. Dransfield ◽  
C. Haslett ◽  
A.G. Rossi
Keyword(s):  
Nuclear Factor Κb ◽  
Resolution Of Inflammation ◽  
Tnf Α ◽  
Successful Resolution ◽  
Factor Α ◽  
Apoptotic Effects ◽  
Second Wave ◽  
Crucial Part

Granulocyte apoptosis is a crucial part of the successful resolution of inflammation. In vitro results show that activation of NF-κB (nuclear factor κB) in granulocytes is a survival mechanism. NF-κB inhibitors increase the rate of constitutive apoptosis in neutrophils and eosinophils and cause these cells to respond to the pro-apoptotic effects of TNF-α (tumour necrosis factor-α). Results from both in vivo and in vitro experiments suggest that there are at least two important waves of NF-κB activation in inflammatory loci, which increase the expression of COX-2 (cyclooxygenase-2), itself an NF-κB controlled gene. The first wave causes the production of inflammatory mediators such as PGE2 (prostaglandin E2), allowing the establishment of inflammation. The second wave causes the synthesis of PGD2 and its metabolites that induce granulocyte apoptosis by inhibiting NF-κB activation. These metabolites may therefore be important physiological mediators controlling the resolution of inflammation. Although NF-κB is an important target for anti-inflammatory therapy, the timing of inhibition in vivo may be crucial, to ensure that production of PGD2 and its sequential metabolites can occur.

scholarly journals Effect of GCSB-5, a Herbal Formulation, on Monosodium Iodoacetate-Induced Osteoarthritis in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Joon-Ki Kim ◽  
Sang-Won Park ◽  
Jung-Woo Kang ◽  
Yu-Jin Kim ◽  
Sung Youl Lee ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Protein Expression ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Cartilage Explants ◽  
Therapeutic Effects ◽  
Monosodium Iodoacetate ◽  
Factor Α

Therapeutic effects of GCSB-5 on osteoarthritis were measured by the amount of glycosaminoglycan in rabbit articular cartilage explantsin vitro, in experimental osteoarthritis induced by intra-articular injection of monoiodoacetate in ratsin vivo. GCSB-5 was orally administered for 28 days.In vitro, GCSB-5 inhibited proteoglycan degradation. GCSB-5 significantly suppressed the histological changes in monoiodoacetate-induced osteoarthritis. Matrix metalloproteinase (MMP) activity, as well as, the levels of serum tumor necrosis factor-α, cyclooxygenase-2, inducible nitric oxide synthase protein, and mRNA expressions were attenuated by GCSB-5, whereas the level of interleukin-10 was potentiated. By GCSB-5, the level of nuclear factor-κB p65 protein expression was significantly attenuated but, on the other hand, the level of inhibitor of κB-α protein expression was increased. These results indicate that GCSB-5 is a potential therapeutic agent for the protection of articular cartilage against progression of osteoarthritis through inhibition of MMPs activity, inflammatory mediators, and NF-κB activation.

scholarly journals Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML

2014 ◽  
Vol 211 (6) ◽  
pp. 1093-1108 ◽  
Author(s):  
Andrew Volk ◽  
Jing Li ◽  
Junping Xin ◽  
Dewen You ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Leukemic Cells ◽  
Comprehensive Treatment ◽  
Hematopoietic Stem ◽  
Similar Treatment ◽  
Stem And Progenitor Cells ◽  
Treatment Paradigm ◽  
Factor Α

Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK–AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF–JNK–AP1 signaling pathway. Our data suggest that co-inhibition of both TNF–JNK–AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.

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