c-Jun N-terminal kinase – c-Jun pathway transactivates Bim to promote osteoarthritis

Osteoarthritis (OA) is a chronic degenerative joint disorder. Previous studies have shown abnormally increased apoptosis of chondrocytes in patients and animal models of OA. TNF-α and nitric oxide have been reported to induce chondrocyte ageing; however, the mechanism of chondrocyte apoptosis induced by IL-1β has remained unclear. The aim of this study is to identify the role of the c-Jun N-terminal kinase (JNK) – c-Jun pathway in regulating induction of Bim, and its implication in chondrocyte apoptosis. This study showed that Bim is upregulated in chondrocytes obtained from the articular cartilage of OA patients and in cultured mouse chondrocytes treated with IL-1β. Upregulation of Bim was found to be critical for chondrocyte apoptosis induced by IL-1β, as revealed by the genetic knockdown of Bim, wherein apoptosis was greatly reduced in the chondrocytes. Moreover, activation of the JNK–c-Jun pathway was observed under IL-1β treatment, as indicated by the increased expression levels of c-Jun protein. Suppression of the JNK–c-Jun pathway, using chemical inhibitors and RNA interference, inhibited the Bim upregulation induced by IL-1β. These findings suggest that the JNK–c-Jun pathway is involved in the upregulation of Bim during OA and that the JNK–c-Jun–Bim pathway is vital for chondrocyte apoptosis.

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Nitric oxide in cyclosporine A-induced hypertension: role of protein kinase C

American Journal of Hypertension ◽

10.1016/s0895-7061(99)00089-8 ◽

1999 ◽

Vol 12 (11) ◽

pp. 1091-1097 ◽

Cited By ~ 21

Author(s):

G Oriji

Keyword(s):

Nitric Oxide ◽

Protein Kinase C ◽

Protein Kinase ◽

Cyclosporine A ◽

Kinase C ◽

Induced Hypertension

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Up-regulation of P21-activated kinase 1 in osteoarthritis chondrocytes is responsible for osteoarthritic cartilage destruction

Bioscience Reports ◽

10.1042/bsr20191017 ◽

2020 ◽

Vol 40 (1) ◽

Author(s):

Wanli Ma ◽

Xiaohe Wang ◽

Chunhui Wang ◽

Mingzhi Gong ◽

Peng Ren

Keyword(s):

Articular Cartilage ◽

Cartilage Destruction ◽

Related Factors ◽

Osteoarthritic Cartilage ◽

Resident Cell ◽

Joint Disorder ◽

Osteoarthritis Chondrocytes ◽

P21 Activated Kinase ◽

Pak1 Expression

Abstract Osteoarthritis is mainly caused by a degenerative joint disorder, which is characterized by the gradual degradation of articular cartilage and synovial inflammation. The chondrocyte, the unique resident cell type of articular cartilage, is crucial for the development of osteoarthritis. Previous studies revealed that P21-activated kinase-1 (PAK1) was responsible for the initiation of inflammation. The purpose of the present study was to determine the potential role of PAK1 in osteoarthritis. The level of PAK1 expression was measured by Western blot and quantitative real-time PCR in articular cartilage from osteoarthritis model rats and patients with osteoarthritis. In addition, the functional role of aberrant PAK1 expression was detected in the chondrocytes. We found that the expression of PAK1 was significantly increased in chondrocytes treated with osteoarthritis-related factors. Increased expression of PAK1 was also observed in knee articular cartilage samples from patients with osteoarthritis and osteoarthritis model rats. PAK1 was found to inhibit chondrocytes proliferation and to promote the production of inflammatory cytokines in cartilages chondrocytes. Furthermore, we found that PAK1 modulated the production of extracellular matrix and cartilage degrading enzymes in chondrocytes. Results of the present studies demonstrated that PAK1 might play an important role in the pathogenesis of osteoarthritis.

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TNF-α Activating Osteoclasts in Patients with Psoriatic Arthritis Enhances the Recruitment of Osteoclast Precursors: A Plausible Role of WNT5A-MCP-1 in Osteoclast Engagement in Psoriatic Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms23020921 ◽

2022 ◽

Vol 23 (2) ◽

pp. 921

Author(s):

Shang-Hung Lin ◽

Ji-Chen Ho ◽

Sung-Chou Li ◽

Yu-Wen Cheng ◽

Chung-Yuan Hsu ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Rna Interference ◽

Joint Destruction ◽

Neutralizing Antibody ◽

Healthy Controls ◽

Osteoclast Precursors ◽

Tnf Α ◽

Wnt Ligands

Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. The number of CD68+WNT5A+ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-α but not IL-17. We conclude that TNF-α recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA.

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The role of nitric oxide, reactive oxygen species, and protein kinase C in oxytocin-induced cardioprotection in ischemic rat heart

Peptides ◽

10.1016/j.peptides.2012.08.001 ◽

2012 ◽

Vol 37 (2) ◽

pp. 314-319 ◽

Cited By ~ 27

Author(s):

Mahdieh Faghihi ◽

Ali Mohammad Alizadeh ◽

Vahid Khori ◽

Mostafa Latifpour ◽

Saeed Khodayari

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Protein Kinase C ◽

Protein Kinase ◽

Rat Heart ◽

Reactive Oxygen ◽

Oxygen Species ◽

Kinase C

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Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.4.h1211 ◽

2000 ◽

Vol 278 (4) ◽

pp. H1211-H1217 ◽

Cited By ~ 57

Author(s):

Roby D. Rakhit ◽

Richard J. Edwards ◽

James W. Mockridge ◽

Anwar R. Baydoun ◽

Amanda W. Wyatt ◽

...

Keyword(s):

Nitric Oxide ◽

Ventricular Myocytes ◽

Culture Conditions ◽

Neonatal Rat ◽

No Donor ◽

Rat Ventricular Myocytes ◽

Kinase C ◽

Neonatal Rat Ventricular Myocytes ◽

Oxide Synthase

The aim of this study was to investigate the role of nitric oxide (NO) in a cellular model of early preconditioning (PC) in cultured neonatal rat ventricular myocytes. Cardiomyocytes “preconditioned” with 90 min of stimulated ischemia (SI) followed by 30 min reoxygenation in normal culture conditions were protected against subsequent 6 h of SI. PC was blocked by N G-monomethyl-l-arginine monoacetate but not by dexamethasone pretreatment. Inducible nitric oxide synthase (NOS) protein expression was not detected during PC ischemia. Pretreatment (90 min) with the NO donor S-nitroso- N-acetyl-l,l-penicillamine (SNAP) mimicked PC, resulting in significant protection. SNAP-triggered protection was completely abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) but was unaffected by chelerythrine or the presence of glibenclamide and 5-hydroxydecanoate. With the use of RIA, SNAP treatment increased cGMP levels, which were blocked by ODQ. Hence, NO is implicated as a trigger in this model of early PC via activation of a constitutive NOS isoform. After exposure to SNAP, the mechanism of cardioprotection is cGMP dependent but independent of protein kinase C or ATP-sensitive K+ channels. This differs from the proposed mechanism of NO-induced cardioprotection in late PC.

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The role of protein kinase C isozymes in TNF-α-induced cytotoxicity to a rat intestinal epithelial cell line

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.280.4.g572 ◽

2001 ◽

Vol 280 (4) ◽

pp. G572-G583 ◽

Cited By ~ 16

Author(s):

Q. Chang ◽

B. L. Tepperman

Keyword(s):

Epithelial Cell ◽

Caspase 3 ◽

Cell Injury ◽

Cell Damage ◽

Epithelial Cell Line ◽

Intestinal Epithelial ◽

Kinase C ◽

Pkc Isoforms ◽

Tnf Α

Tumor necrosis factor (TNF)-α can induce cytotoxicity and apoptosis in a number of cell types and has been implicated in the regulation of many inflammatory processes. It has been suggested that protein kinase C (PKC) is one of the intracellular mediators of the actions of TNF-α. In the present study, the role of PKC isoforms in TNF-α-mediated cytotoxicity and apoptosis in intestinal cells was investigated using the rat epithelial cell line, IEC-18. Cells were incubated with TNF-α in the presence or absence of the transcription inhibitor actinomycin D (AMD). The extent of cell damage was enhanced when AMD was added to incubation medium, suggesting that new protein synthesis plays a role in the cytotoxic action of TNF. TNF-α also induced the translocation of PKC-α, -δ, and -ε from cytosol to the membrane fraction of the intestinal cells. Furthermore, the cytotoxic and apoptotic effects of TNF were reduced by pretreating the cells with the PKC-ε translocation inhibitor, PKC-εV1–2. In contrast, although cells incubated with the phorbol ester phorbol 12-myristate 13-acetate (PMA) also displayed an increase in cell injury, the extent of cytotoxicity and apoptosis was not enhanced by AMD. Furthermore, PMA-induced cell damage was reduced by rottlerin, a PKC-δ inhibitor. Caspase-3, an enzyme implicated in the mediation of apoptosis, was activated in cells in response to either TNF-α or PMA stimulation, and its effects on this activity were reduced by selective inhibition of PKC-ε and -δ, respectively. Furthermore, inhibition of caspase-3 activity reduced apoptosis. These data suggest that activation of selective PKC isoforms mediate the effects of TNF-α on intestinal epithelial cell injury.

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Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.1.r265 ◽

1999 ◽

Vol 276 (1) ◽

pp. R265-R276 ◽

Cited By ~ 33

Author(s):

Anand Kumar ◽

Rupinder Brar ◽

Peter Wang ◽

Linda Dee ◽

Greg Skorupa ◽

...

Keyword(s):

Nitric Oxide ◽

Septic Shock ◽

Cardiac Myocytes ◽

Guanylate Cyclase ◽

Cardiac Myocyte ◽

Intracellular Cgmp ◽

Human Septic Shock ◽

Tnf Α ◽

Myocyte Contractility

Previous studies have demonstrated the existence of a circulating myocardial depressant substance during human septic shock. We have recently identified this substance as a synergistic combination of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study utilized an in vitro cardiac myocyte assay to evaluate the potential mechanistic role of nitric oxide (NO) and cGMP in depression of myocyte contractility induced by TNF-α, IL-1β, TNF-α + IL-1β (at low concentrations), and human septic shock serum (HSS). TNF-α, IL-1β, TNF-α + IL-1β, and each of 5 sera from patients with acute septic shock caused depression of both maximum extent and peak velocity of cardiac myocyte shortening and an increase in intracellular cGMP concentration during 30 min of exposure (minimum P < 0.01). NO synthetase (NOS) and guanylate cyclase inhibitors such as N-methyl-l-arginine (l-NMA) and methylene blue prevented these effects; an excess ofl-arginine withl-NMA restored them (minimum P < 0.01). In contrast,d-arginine failed to reestablish cytokine-induced myocyte depression and cGMP accumulation prevented byl-NMA. Exposure of myocytes to TNF-α, IL-1β, or TNF-α + IL-1β produced a concentration-dependent increase in intracellular cGMP that paralleled the depression of cardiac myocyte contractility (minimum P < 0.001). In addition, TNF-α, IL-1β, TNF-α + IL-1β, or HSS application to cardiac myocytes resulted in increased NO gas generation, which was inhibited byl-NMA (minimum P < 0.01). Furthermore, unstimulated cardiac myocytes were shown to harbor constitutive but not inducible NOS activity. These data suggest that the sequential generation of NO by a constitutive NOS and cGMP by guanylate cyclase represents an important mechanism of cardiac myocyte depression by TNF-α, IL-1β, TNF-α + IL-1β, and the myocardial depressant substance(s) of septic shock.

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Nitric oxide production in murine spleen cells: role of interferons and prostaglandin E2in the generation of cytotoxic activity

Mediators of Inflammation ◽

10.1155/s0962935196000117 ◽

1996 ◽

Vol 5 (1) ◽

pp. 62-68 ◽

Cited By ~ 1

Author(s):

Dominique Vaillier ◽

Richard Daculsi ◽

Norbert Gualdel

Keyword(s):

Nitric Oxide ◽

Cytotoxic Activity ◽

Minor Role ◽

No Production ◽

Spleen Cells ◽

Kinase C ◽

Murine Spleen ◽

Ifn Γ ◽

A Minor

The production of nitric oxide (NO) was measured in cultures of spleen cells stimulated by lipopolysaccharide (LPS), IL-2 or LPS + IL-2. We observed that NO synthesis is increased by IFN-γ but inhibited by IFN-α/β. This is not the case when IL-2 is present in the cultures, since interferons play a minor role in the regulation of the NO production. When IL-2 and LPS were associated in the cultures, the IFN-α/β role seems more important than that of IFN-γ. PGE2inhibits NO production in LPS supplemented cultures but has a slight effect in the presence of IL-2 and no effect with IL-2 + LPS. 3-isoButyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterases, induces a decrease of IFN production. In the presence of H-7, an inhibitor of protein kinase C (PKC), NO production is reduced when the cultures are supplemented by LPS or IL-2 but not when IL-2 and LPS are both added. H-7 also reduced IFN production. In the presence of NG-monomethyl-L-arginine (N-MMA), an inhibitor of NO synthesis, IFN production was increased, with no change in the cytotoxic activity. Hence, interferons regulate NO production by mouse spleen cells and, in return, NO modulates the generation of IFN.

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