Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis

Melchiorri, Cinzia; Melicòni, Riccardo; Frizziero, L; Silvestri, Tania; Pulsatelli, Lia; Mazzetti, Ilaria; Borzı̀, Rosa Maria; Uguccioni, Mariagrazia; Facchini, Andrea

doi:10.1002/1529-0131(199812)41:12<2165::aid-art11>3.3.co;2-f

Cited by 36 publications

(47 citation statements)

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“…Paradoxically, however, NO has also been proposed to be the cytotoxic species responsible for an increasing number of pathologic disorders, including rheumatic (5) and neurodegenerative (6) diseases. Expression of inducible nitric oxide synthase (iNOS) has been associated with chondrocytes during the pathogenesis of osteoarthritis (OA) (7) and rheumatoid arthritis (RA) (8); however, the exact role of NO in this regard is not fully understood. While it has been reported that NO causes chondrocyte cell death (9,10), other more recent reports have proposed NO to be a physiologic regulator of mitochondrial respiration in chondrocytes (11,12).…”

mentioning

confidence: 99%

Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Carlo

Loeser

2002

Arthritis & Rheumatism

227

178

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Objective. Chondrocyte cell death, possibly related to increased production of endogenous nitric oxide (NO), has been observed during the pathogenesis of osteoarthritis and rheumatoid arthritis. The purpose of this study was to investigate the potential role of NO in causing chondrocyte cell death and to determine the contribution of other reactive oxygen species (ROS).Methods. Cell death and cytotoxicity were evaluated in human articular chondrocytes in response to various NO donor compounds with and without agents that stimulate or inhibit the production of additional ROS using both the alginate bead and the monolayer culture systems. Cell death was quantified by a total cell count with fluorescent labels, and cytotoxicity was measured as a function of cellular NADH-and NADPHdependent dehydrogenase activity. To determine if the redox status of the chondrocyte could influence the observed effect of NO, cells were preincubated for 24 hours in L-cystine-and glutathione (GSH)-depleted media to reduce intracellular GSH levels, a major defense mechanism against oxidative stress. Apoptosis was analyzed with the quantification of histoneassociated DNA fragments. Conclusion. These results show that NO by itself is not cytotoxic to cultured chondrocytes and can even be protective under certain conditions of oxidative stress. Chondrocyte cell death from NO occurs under conditions where other ROS are also generated. Results. Treatment of chondrocytes with peroxynitrite (ONOONitric oxide (NO) participates in the normal functioning of a wide array of mammalian processes, including vasodilation, inhibition of platelet aggregation, neurotransmission, and macrophage-mediated immunity (1-4). Paradoxically, however, NO has also been proposed to be the cytotoxic species responsible for an increasing number of pathologic disorders, including rheumatic (5) and neurodegenerative (6) diseases. Expression of inducible nitric oxide synthase (iNOS) has been associated with chondrocytes during the pathogenesis of osteoarthritis (OA) (7) and rheumatoid arthritis (RA) (8); however, the exact role of NO in this regard is not fully understood. While it has been reported that NO causes chondrocyte cell death (9,10), other more recent reports have proposed NO to be a physiologic regulator of mitochondrial respiration in chondrocytes (11,12). Moreover, production of high levels of endogenous NO by overexpression of the iNOS gene in transfected chondrocytes did not cause cell death (13).The direct investigation of the function of exogenous NO production on chondrocytes has been hampered by the lack of uniformity that exists between the different types of NO donor compounds. Knowledge of the precise reactive nitrogen species (RNS) that is

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mentioning

confidence: 99%

Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Carlo

Loeser

2002

Arthritis & Rheumatism

227

178

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“…Recent observations by this and other laboratories indicate that, despite the general absence of clinical signs of inflammation, chondrocytes derived from patients with OA, show superinduction of proinflammatory genes typically associated with the products of synovial tissues in rheumatoid arthritis, including nitric-oxide synthase, cyclooxygenase-2, TNF␣, IL-6, and IL-8. The spontaneous production of the corresponding gene products and inflammatory mediators promotes a catabolic state, which leads to progressive cartilage damage in OA (1)(2)(3)(4). This intraarticular inflammatory response in OA-affected cartilage, which may be considered as an in situ "molecular inflammation," is partially dependent on autocrine IL-1␤ production, which induces and sustains an imbalance of cartilage homeostasis and extracellular matrix synthesis (5).…”

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confidence: 99%

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Attur¹,

Dave²,

Cipolletta³

et al. 2000

Journal of Biological Chemistry

119

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Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1␤-induced nitric oxide (NO) and/or prostaglandin E 2 production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC 50 for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1␤ mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance. Osteoarthritis (OA)1 is considered a non-inflammatory arthritis, characterized by a limited infiltration of neutrophils into the synovial space and, in general, an absence of the classical signs of inflammation. Chondrocytes embedded within articular cartilage that is avascular and aneural reside in a sequestered environment, perhaps more than other cell types, whereby cellular metabolism is regulated by an autocrine mechanism responsive to biomechanical and pericellular signals. Recent observations by this and other laboratories indicate that, despite the general absence of clinical signs of inflammation, chondrocytes derived from patients with OA, show superinduction of proinflammatory genes typically associated with the products of synovial tissues in rheumatoid arthritis, including nitric-oxide synthase, cyclooxygenase-2, TNF␣, IL-6, and IL-8. The spontaneous production of the corresponding gene products and inflammatory mediators promotes a catabolic state, which leads to progressive cartilage damage in OA (1-4). This intraarticular inflammatory response in OA-affected cartilage, which may be considered as an in situ "molecular inflammation," is partially dependent on autocrine IL-1␤ production, which induces and sustains an imbalance of cartilage homeostasis and extracellular matrix synthesis (5). The autocrine production of IL-1 in OA-affected cartilage is amplified by engagement of integrins such as ␣ 5 ␤ 1 by abnormally expressed extracellular matrix proteins, including proteolytic fragments of fibronectin (5, 6)...

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“…(8) Each of the cytokines listed in 7 above, act directly and/or indirectly to stimulate the transcription of the iNOS gene, acting in some cytokines via the doubleheaded arrow linking them to NF-B and, also, acting in some cytokines directly on iNOS induction [1,5,[37][38][39][40][41][42].…”

Section: �� Eci�c �� − Cycle Mechanismsmentioning

confidence: 99%

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

Pall

2013

ISRN Hypertension

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e NO/ONOO − cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic in�ammatory diseases. is paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. e cycle involves 12 elements, including superoxide, peroxynitrite (ONOO − ), nitric oxide (NO), oxidative stress, NF-B, in�ammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. is extraordinary �t to the principles of the NO/ONOO − cycle allows one to conclude that PAH is a NO/ONOO − cycle disease, and this �t supports the cycle as a ma�or paradigm of chronic in�ammatory disease.

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Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis

Cited by 36 publications

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Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

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Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis

Cited by 36 publications

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Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

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Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review