Induction of Nitric Oxide Synthase in Human Chondrocytes

Palmer, Richard; Hickery, Mark S.; Charles, Ian G.; Moncada, Salvador; Bayliss, Michael T.

doi:10.1006/bbrc.1993.1637

Cited by 268 publications

(146 citation statements)

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“…A number of synovial cytokines, including IL-1 ␤ and TNF-␣ , or endotoxins (LPS) enhance PGE 2 and NO synthesis in cultured chondrocytes (9,10). In the present study, we first examined whether cartilage slices from normal human cartilage responded in a similar fashion.…”

Section: Resultsmentioning

confidence: 99%

“…The human articular chondrocytes, when stimulated with cytokines and/or endotoxin in vitro, release various inflammatory mediators, including nitric oxide (NO) and PGE 2 (9,10). We (11) and others (12) have recently observed that OAaffected cartilage in ex vivo conditions spontaneously releases NO in quantities sufficient to cause cartilage damage.…”

Section: Introductionmentioning

confidence: 99%

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Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Amin¹,

Attur²,

Patel³

et al. 1997

J. Clin. Invest.

355

285

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Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE 2 at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage ϩ cytokines ϩ endotoxin. The superinduction of PGE 2 production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE 2 by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE 2 production, and not NO, in OA-affected cartilage. The NO synthase inhibitor H N G -monomethyl-L -arginine monoacetate inhibited OA cartilage NO production by Ͼ 90%, but augmented significantly (twofold) the spontaneous production of PGE 2 in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE 2 production. Cytokine ϩ endotoxin stimulation of OA explants increased PGE 2 production above the spontaneous release. Addition of L -NMMA further augmented cytokine-induced PGE 2 production by at least fourfold. Inhibition of PGE 2 by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE 2 did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows ( a ) superinduction of PGE 2 due to upregulation of COX-2, and ( b ) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE 2 . These studies, together with others, also suggest that PGE 2 may be differentially regulated in normal and OA-affected chondrocytes. ( J. Clin. Invest. 1997. 99:1231-1237.)

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Amin¹,

Attur²,

Patel³

et al. 1997

J. Clin. Invest.

355

285

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“…Mononuclear phagocytes and chondrocytes are the most likely sources in the joint. Human articular chondrocytes produce relatively high levels of NO in response to cytokines (11,36,37). If NO is a vital mediator of joint inflammation in RA, then blocking NO production by NOS2-specific inhibitors and blocking NO effects by NO quenchers may have therapeutic roles in RA.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients.

Clair

Wilkinson

Lang

et al. 1996

The Journal of Experimental Medicine

136

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SummaryNitric oxide (NO) is an important inflammatory mediator in nonhuman animal models of rheumatoid arthritis (RA). The purpose of the present study was to determine whether blood mononuclear cells from patients with active RA (as compared to control subjects) have higher levels of NO synthase type 2 (NOS2) and produce more NO in vitro. Leukocytes from 25 RA patients and 20 normal subjects were examined. Arthritis activity was assessed by tender and swollen joint counts, duration of morning stiffness, patient assessment of pain, physician and patient global assessment of disease activity, the modified Stanford Health Assessment Questionnaire, and by blood levels of acute phase reactants. Blood mononuclear cell NOS enzyme activity/antigen content and nitrite/nitrate formation in vitro were measured. Blood mononuclear cells from RA patients had increased NOS activity and increased NOS2 antigen content as compared to those from normal subjects, and responded to interferon-'y with increased NOS expression and nitrite/nitrate production in vitro. NOS activity of freshly isolated blood mononuclear cells correlated significantly with disease activity, as assessed by tender and swollen joint counts. Our results demonstrate that patients with RA have systemic activation for NOS2 expression, and that the degree of activation correlates with disease activity. Increased NOS2 expression and NO generation may be important in the pathogenesis of RA.R heumatoid arthritis (RA) is a chronic systemic disease of unknown etiology that is characterized by joint inflammation and progressive loss of articular cartilage and subchondral bone (1). Prominent pathologic features of joint inflammation are synovial proliferation and mononuclear cell infiltration, which are believed to result from dysregulated production of cytokines, growth factors, cell adhesion molecules, and nonprotein mediators, such as arachidonic acid metabolites and reactive oxygen species (2-4).Nitric oxide (NO) may be a critical mediator in this inflammatory cascade (5, 6). NO is generated endogenously from L-arginine by oxidation to L-citrulline and NO. This reaction is catalyzed by a group of three related NO synthase (NOS) enzymes that are encoded by separate genes (neural NOS [NOS1], endothelial NOS [NOS3], and inducible NOS or NOS type 2 [NOS2]). Increased NOS2 expression and NO production have been noted in induced and spontaneous nonhuman animal models of arthritis, and inhibitors of NOS can reduce arthritis in these conditions (6-12). Moreover, serum and synovial fluid from humans with inflammatory arthritides have increased levels of NO catabolites (13-15). Also, synovial tissue from humans with inflammatory arthritis express NOS2 mRNA and protein, and generate NO in vitro (16).The purpose of the present study was to determine whether blood mononuclear cells from patients with active RA have enhanced expression of NOS2 and enhanced capability to produce NO in vitro. We report results of work that couples detailed clinical and laboratory rheumatological st...

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“…'9 Furthermore, only 40-60% of the ingested nitrate appeared in urine,'9 20 which helps to explain why people taking a diet high in nitrate excrete less nitrate in the urine than they ingest. '9 (28) mm/lst h, joint count 20 (6), and early morning stiffness 4 (2) h). Tables 1 and 2 summarise the epidemiological, drug treatment, clinical, and laboratory data of each patient.…”

Section: Introductionmentioning

confidence: 99%

Urinary nitrate excretion is increased in patients with rheumatoid arthritis and reduced by prednisolone.

Stichtenoth

Fauler

Zeidler

et al. 1995

Annals of the Rheumatic Diseases

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Objectives-To determine daily production of nitric oxide (NO) measured as urinary nitrate excretion, and the effect of prednisolone in patients with rheumatoid arthritis (RA). Methods-Twenty four hour urinary nitrate was measured by gas chromatography in 10 patients with RA, before and two to four weeks after commencement of prednisolone 0 5 mg/kg body weight, and in 18 healthy controls. Results-Before the start of prednisolone treatment the urinary nitrate excretion in patients with RA was 2*7-fold greater (p < 0.001) than that in healthy volunteers.After prednisolone it decreased significantly, by 28%, at which time inflammatory activity (as indicated by C reactive protein, erythrocyte sedimentation rate, joint count, and early morning stiffness) was also reduced considerably. Despite this decrease, the urinary nitrate excretion in patients with RA remained twice that in the control group (p < 0 05). Conclusion-Our data suggest that the endogenous production ofNO is enhanced in patients with RA. Furthermore, the results indicate that, in parallel with suppression of inflammation, this increased NO synthesis could be reduced by prednisolone treatment. is readily oxidised to nitrite and nitrate,'8 which are excreted rapidly into the urine. This endogenous nitrate synthesis explains the finding, made before discovery of the NO pathway, that people taking diets low in nitrate excrete four fold more nitrate in the urine than the amount ingested in their diet. '9 Furthermore, only 40-60% of the ingested nitrate appeared in urine,'9 20 which helps to explain why people taking a diet high in nitrate excrete less nitrate in the urine than they ingest.'9 To summarise: in the absence of excess dietary nitrate intake, the major source of urinary nitrate is endogenously synthesised NO.2' 22 NO synthase activity can therefore be reliably and noninvasively assessed by measurement of urinary nitrate excretion.23 In the present study we determined urinary nitrate excretion and the effect of prednisolone in patients with RA.

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Induction of Nitric Oxide Synthase in Human Chondrocytes

Cited by 268 publications

References 0 publications

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients.

Urinary nitrate excretion is increased in patients with rheumatoid arthritis and reduced by prednisolone.

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