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However, in the presence of the NOS inhibitor N G -monomethyl- L -arginine L -NMA , the ILinduced inhibition of proteoglycan synthesis was completely reversed in the deep zone whereas only a partial effect was observed in the superficial zone.

In addition, exposure to L -NMA and IL-1 together reduced the metabolic half-life of proteoglycans in the deep and superficial zones, despite the differing effects on proteoglycan inhibition. Finally, the authors observed that NO production in response to IL-1 stimulation declined with age.

These findings led the authors to suggest that NO may not mediate extracellular matrix turnover identically throughout articular cartilage and, perhaps, plays a protective role in proteoglycan catabolism [ 22 ]. Intriguingly, chondrocytes not only respond differently to NO based on their location in the cartilage, but different effects on cartilage can be elicited depending on the method used to inhibit inflammation.

Bezerra and coworkers [ 23 ] examined the effects of NO and peroxynitrite in zymosan-induced arthritis, and found that the addition of both NO and peroxynitrite induced inflammation as measured by histopathology and the glycosaminoglycan content of the cartilage. Furthermore, when a nonselective NOS inhibitor or a selective iNOS inhibitor was added, the synovitis was improved but the glycosaminoglycan loss was enhanced.

This indicates that although blocking NO production helps to decrease inflammation, cartilage damage is enhanced. Finally, when the peroxynitrite scavenger uric acid was added, both the synovitis and glycosaminoglycan loss was ameliorated, suggesting that inhibiting peroxynitrite production may be a more effective target for protecting against inflammation and cartilage loss in this arthritis model [ 23 ].

Again, these experiments, combined with the different behavior associated with chondrocyte location in the joint, suggest that the role played by NO in the joint may be more complicated than previously understood and that more research is needed.

In addition to contributing to the breakdown of the extracellular matrix, NO also mediates apoptosis. Both exogenous and endogenous NO can induce apoptosis via a mitochondria-dependent mechanism [ 24 , 25 ]. Studies demonstrated that incubation of human articular chondrocytes with the NO donor sodium nitroprusside SNP induced events characteristic of apoptosis, including increasing caspase-3 and caspase-7 expression and downregulating Bcl-2 expression [ 25 ].

Further examination of the mechanisms by which SNP induces apoptosis illustrated that SNP induced DNA fragmentation, cytoskeletal remodeling, mitochondrial dysfunction, caspase activation, and cytochrome c release [ 26 ], all of which are hallmarks of apoptosis.

Treatment with a NO scavenger significantly decreased multiple aspects of SNP-induced cell damage [ 26 ], once again demonstrating the pleiotropic effects of NO.

Interestingly, del Carlo and Loeser [ 12 ] found that incubation with NO alone does not induce apoptotic cell death in chondrocytes.

In these experiments, incubation of chondrocytes with the NO donors SNP and 3-morpholiosydnonimine SIN-1 , as well as the ROS peroxynitrite, all induced apoptosis. However, both SNP and SIN-1 also generate ROS and are not considered to be sources of pure NO.

Specifically, SIN-1 generates superoxide in addition to NO [ 27 , 28 ], which can then interact with NO to generate peroxynitrite. In support of this, treatment with either peroxynitrite or superoxide scavengers resulted in protection against apoptosis caused by incubation with SIN-1 but not with SNP.

Intriguingly, incubation with diazeniumdiolates NOC compounds , which are reliable sources of NO, did not cause cell death and the NOC compounds protected against oxidative stress, perhaps by suppressing chondrocyte energy metabolism. This study demonstrated that both NO and ROS are required to induce apoptosis, suggesting that NO alone may have beneficial effects in chondrocytes [ 12 ].

Other studies on the effect of NO on chondrocyte apoptosis have focused on the role of apoptosis in terminal differentiation, again illustrating a nonpathological role for NO in development. An increase in inorganic phosphate was shown to induce apoptosis in terminally differentiated epiphyseal chondrocytes [ 29 ].

Subsequent studies demonstrated that inorganic phosphate increased both nitrate and nitrite concentrations, and this increase was attenuated when either NOS activity or phosphate transport was inhibited.

In addition, inorganic phosphate increased caspase-3 activity and decreased the mitochondrial membrane potential, whereas NOS inhibitors maintained mitochondrial function, illustrating that NO mediates phosphate-dependent chondrocyte apoptosis [ 29 ]. ROS have been shown to have deleterious effects on cells and to contribute to chondrocyte death.

Davies and colleagues [ 30 ] demonstrated that OA cartilage has significantly more DNA damage than normal cartilage, and that this damage was mediated by IL-1 and, ultimately, by ROS.

Porcine articular cartilage was harvested from normal tissue and compared with cartilage harvested from OA tissue and the number of single-stranded and double-stranded DNA breaks was analyzed. In cells from healthy cartilage, increasing concentrations of IL-1 correlated with increasing NO concentrations and increasing DNA damage.

The increase in DNA damage was attenuated by incubation with the specific iNOS inhibitor W and the superoxide scavenger SOD, suggesting that superoxide may have a role in generating DNA breaks.

It is not clear, however, what effect DNA damage has on OA cells and the disease process. The authors suggested that DNA damage could alter transcription by increasing errors, which could result in dysfunctional proteins, or alternatively by inhibiting the binding of transcription factors to promoter regions [ 30 ].

There is some evidence that the degenerative activity attributed to an increase in NO concentration could be a result of an increase in the concentration of RNOS. Clancy and coworkers [ 31 ] demonstrated that NO and peroxynitrite have opposing effects on nuclear factor-κB NF-κB activation in chondrocyte cultures.

The transcription factor NF-κB is activated rapidly in response to inflammatory stimuli such as IL-1β and TNF-α and upregulates the transcription of a number of genes involved in cartilage degradation including iNOS, matrix metalloproteinases and COX-2, as well as IL-1β and TNF-α.

Inactive NF-κB is sequestered in the cytoplasm by its inhibitor IκB. Upon activation, IκB is phosphorylated and degraded, which allows NF-κB to translocate to the nucleus and bind to its target DNA sequences. These experiments suggest that NO is not required for immediate activation of NF-κB and suggest that its catabolic activity could be mediated in part through peroxynitrite [ 31 ].

Effects of peroxynitrite and the NO donor SCNEE on IL-1β stimulated NF-κB p65 nuclear translocation. NF-κB, nuclear factor-κB; NO, nitric oxide; PN, peroxynitrite; SCNEE, S -nitrosocysteine ethyl ester.

Reproduced with permission from Clancy and coworkers [ 31 ]. Another group analyzed the differential roles of hydrogen peroxide and superoxide in ILinduced NF-κB activation. Mendes and colleagues [ 32 ] found that IL-1 stimulation resulted in an increase in both hydrogen peroxide and superoxide in bovine articular chondrocytes, although only superoxide was required for NF-κB activation and iNOS expression.

This conclusion is supported by the fact that SOD inhibited ILinduced IκB degradation. Like Clancy and coworkers [ 31 ], this group also found that NO alone inhibits NF-κB activation and iNOS expression [ 33 ], but they suggested that because the concentration of NO immediately after IL-1 stimulation appeared to be quite low, it was unlikely that significant quantities of peroxynitrite were generated.

This led them to suggest that peroxynitrite is not likely to be required for NF-κB activation in chondrocytes. However, these results do not exclude the possibility that peroxynitrite is able to activate NF-κB, merely that it may not be required.

These results clearly demonstrate the difficulty in teasing out the specific roles played by both NO and ROS in order to determine their involvement in ILinduced NF-κB activation. Peroxynitrite also helps perpetuate the inflammatory process in mesenchymal progenitor cells MPCs , which are used as a model of cartilage and cartilage repair cells.

Whiteman and coworkers [ 34 ] used MPCs to investigate the cellular role of peroxynitrite-modified collagen-II, a biomarker discovered in the serum of patients with both OA and rheumatoid arthritis.

The authors showed that the addition of peroxynitrite-modified collagen-II to MPC cultures induced both iNOS expression and cyclo-oxygenase COX -2 synthesis and that specific iNOS and COX-2 inhibitors blocked this synthesis.

Whiteman and coworkers [ 34 ] suggest that this newly identified proinflammatory pathway may be a target for the development of new therapies for the inflamed joint, reiterating the complexity of NO signaling and the need for continuing research to more fully elucidate the role of NO and its derivatives in cellular physiology and pathophysiology.

Although there is experimental evidence to suggest a catabolic function for NO in the joint, there is also evidence that NO and its derivatives may play a protective role in chondrocytes. In addition, NO has beneficial functions in other tissues, and these activities could potentially occur in chondrocytes as well.

Wound healing experiments showed that supplemental L -arginine injected into animals with dorsal wounds significantly increased both wound-breaking strength and collagen deposition compared with animals injected with saline, although there was no change in plasma NO concentration [ 35 ].

NO was also shown to enhance collagen synthesis in human tendon cells in vitro. When cells harvested from the torn edges of tendons from patients undergoing rotating cuff surgery were transfected with an adenovirus containing the gene for iNOS Ad-iNOS or treated with the NO donor S -nitroso- N -acetylpenicillamine SNAP , total protein and collagen synthesis was enhanced, although higher doses did inhibit collagen synthesis [ 36 ].

These findings were supported by a small randomized double-blind clinical trial in which the same group found that application of a patch containing the NO donor glyceryl trinitrate significantly improved outcomes in patients with supraspinatus tendonopathy compared with patients who received placebo [ 37 ].

This illustrates that the benefits of exogenous NO in tendons is not simply an in vitro effect. Muscará and colleagues [ 38 ] also demonstrated that exogenous NO is beneficial in a rat wound healing model.

The investigators compared the effects of the cyclo-oxygenase-inhibiting nitric oxide donating CINOD agent naproxcinod to its parent compound naproxen on wound healing. Despite inhibiting prostaglandin synthesis to the same extent as naproxen, naproxcinod significantly enhanced collagen deposition at the wound site whereas naproxen decreased collagen deposition, illustrating once again that exogenous NO may help to increase collagen deposition under some conditions.

These studies suggest that perhaps there are some conditions in which NO donors could induce collagen deposition in chondrocytes. Studies have also suggested that exposure to low levels of NO could be protective against subsequent oxidative stress.

Tai and coworkers [ 39 ] demonstrated that NO helps to regulate osteoblast activity. Pretreatment of cultured osteoblasts with a low concentration of the NO donor SNP 0.

However, when osteoblasts were pretreated with the low concentration of SNP and then subjected to the high concentration, cell viability was significantly increased and apoptosis was significantly decreased compared with no pretreatment. This protection was probably mediated via JNKc-Jun-mediated regulation of Bcl-2 gene expression and translocation to the mitochondria.

Interestingly, pretreatment with low concentrations of SNP enhanced the increases in both NO and ROS, demonstrating that the pretreatment is not merely suppressing cellular oxidative stress but in some way protecting against damage.

These experiments again illustrate the complexity of the role played by NO in cellular metabolism as well as the varied responses to ROS in different cell types. As mentioned above, pain is the major determinant in functional disability caused by OA [ 40 ]. NO and RNOS are both involved in perception and reduction of pain, and therefore could be a target for the management of pain in OA.

Hancock and Riegger-Krugh [ 41 ] recently reviewed several potential mechanisms that may explain the role played by NO in pain reduction in patients with OA: the blood-flow pathway is normalized in the presence of NO, which may help to decrease ischemic pain; the nerve transmission pathway, which decreases the irritation of the nerves in the synovium, bone, and soft tissues; the opioid receptor pathway, which might stimulate the body's normal pain reduction pathways; and the anti-inflammation pathway.

The authors concluded that small amounts of transiently produced NO, perhaps produced by endothelial NOS, could potentially decrease the pain associated with OA. However, like the role of NO in the OA disease process, research in this field is still ongoing and there are many outstanding questions.

In addition to NO, RNOS also plays a role in pain and nociception. Wang and coworkers [ 42 ] showed that superoxide is involved in pain deriving from inflammation. Injection of a SOD mimetic M blocked the inflammation, edema, and hyperalgesia associated with carrageenan injection. In addition, the formation of peroxynitrite was also inhibited after injection of M, suggesting that both superoxide and peroxynitrite play a role in the development of inflammation and pain.

Subsequent experiments by the same laboratory showed that the development of morphine-induced tolerance is associated with increased proinflammatory cytokine production as well as oxidative DNA damage [ 43 ].

Inhibition of NO synthesis or the scavenging of superoxide both block the development of morphine-induced tolerance, suggesting that peroxynitrite is involved. This hypothesis was confirmed using a peroxynitrite-decomposition catalyst, which blocked the antinociceptive tolerance response, suggesting once again that decreasing the production of peroxynitrite could help to ameliorate chronic pain.

Peroxynitrite appears to perpetuate the inflammatory process at least in part by helping to induce COX-2 activity. When superoxide or peroxynitrite was injected into rats, the animals developed thermal hyperalgesia, which is associated with tissue damage and inflammation.

The response was blocked by the addition of the NOS inhibitor N G -nitro- L -arginine methyl ester L -NAME , or a peroxynitrite-decomposition catalyst, suggesting that peroxynitrite was responsible for the effect [ 44 ].

Further experiments demonstrated that this led to the activation of NF-κB, which enhanced the expression of the COX-2 but not the COX-1 enzyme. The response was blocked in a dose-dependent manner by the nonselective COX inhibitor indomethacin, the selective COX-2 inhibitor NS, and an anti-prostaglandin E 2 antibody.

These results confirm that peroxynitrite does mediate hyperalgesia associated with inflammation through the COX-prostaglandin E 2 pathway. The role played by NO in the function of normal and pathological joints is still incompletely understood. Although it is clear that NO and RNOS both play a role in the OA disease process, as well as in the perception of pain, studies analyzing the effects of NO-donating agents in both chondrocytes and other cell types are providing insights that suggest that there are also protective functions for NO and its redox derivatives in individual cell types.

Future research into the role played by NO in OA and the utility of NO-donating agents may provide a new therapeutic option for the treatment of OA with an improved risk profile compared with currently available therapies.

Pelletier JP, Martel-Pelletier J, Abramson SB: Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. Article CAS PubMed Google Scholar. Farrell AJ, Blake DR, Palmer RM, Moncada S: Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases.

Ann Rheum Dis. Article PubMed Central CAS PubMed Google Scholar. Maki-Petaja KM, Cheriyan J, Booth AD, Hall FC, Brown J, Wallace SM, Ashby MJ, McEniery CM, Wilkinson IB: Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction.

Int J Cardiol. Google Scholar. Migita K, Yamasaki S, Ida H, Kita M, Hida A, Shibatomi K, Kawakami A, Aoyagi T, Eguchi K: The role of peroxynitrite in cyclooxygenase-2 expression of rheumatoid synovium. Clin Exp Rheumatol. CAS PubMed Google Scholar. Lotito AP, Muscara MN, Kiss MH, Teixeira SA, Novaes GS, Laurindo IM, Silva CA, Mello SB: Nitric oxide-derived species in synovial fluid from patients with juvenile idiopathic arthritis.

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Del Carlo M, Loeser RF: Nitric oxide-mediated chondrocyte cell death requires the generation of additional reactive oxygen species. Pacher P, Beckman JS, Liaudet L: Nitric oxide and peroxynitrite in health and disease. Physiol Rev. Regan EA, Bowler RP, Crapo JD: Joint fluid antioxidants are decreased in osteoarthritic joints compared to joints with macroscopically intact cartilage and subacute injury.

Osteoarthritis Cartilage. Teixeira CC, Ischiropoulos H, Leboy PS, Adams SL, Shapiro IM: Nitric oxide-nitric oxide synthase regulates key maturational events during chondrocyte terminal differentiation. Amin AR, Di Cesare PE, Vyas P, Attur M, Tzeng E, Billiar TR, Stuchin SA, Abramson SB: The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase.

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Taskiran D, Stefanovic-Racic M, Georgescu H, Evans C: Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin Biochem Biophys Res Commun. Ridnour LA, Windhausen AN, Isenberg JS, Yeung N, Thomas DD, Vitek MP, Roberts DD, Wink DA: Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways.

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Hauselmann HJ, Stefanovic-Racic M, Michel BA, Evans CH: Differences in nitric oxide production by superficial and deep human articular chondrocytes: implications for proteoglycan turnover in inflammatory joint diseases. J Immunol. Bezerra MM, Brain SD, Greenacre S, Jeronimo SM, de Melo LB, Keeble J, da Rocha FA: Reactive nitrogen species scavenging, rather than nitric oxide inhibition, protects from articular cartilage damage in rat zymosan-induced arthritis.

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Clancy RM, Gomez PF, Abramson SB: Nitric oxide sustains nuclear factor kappaB activation in cytokine-stimulated chondrocytes. NO is involved in the pathogenesis of inflammatory disorders of the joint, gut and lungs.

Therefore, NO inhibitors represent important therapeutic advance in the management of inflammatory diseases. Selective NO biosynthesis inhibitors and synthetic arginine analogues are proved to be used for the treatment of NO-induced inflammation.

Finally, the undesired effects of NO are due to its impaired production, including in short: vasoconstriction, inflammation and tissue damage. This is a preview of subscription content, log in via an institution to check access.

Rent this article via DeepDyve. Institutional subscriptions. Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, Health Sciences Centre, P. Box , Safat, , Kuwait. Sharma, A. You can also search for this author in PubMed Google Scholar. Correspondence to J. Reprints and permissions.

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NO concentrations are, however, significantly increased in the synovial fluid of a canine OA model [ 8 ]. These findings, in combination with experiments described below, contribute to the prevailing hypothesis that NO is a proinflammatory and proapoptotic factor that, when present in excess, is detrimental to the joint and contributes to OA pathogenesis.

Despite the evidence that NO is primarily a catabolic factor in OA, newer studies have suggested that this view of NO may be too simplistic.

In addition, studies suggest that NO and its reactive oxygen species ROS derivatives may also have opposing effects, both destructive and protective. Finally, there is a small but growing body of literature demonstrating that NO has beneficial effects on other cell types, including tendons and osteoblasts, which could also potentially be present in chondrocytes.

In addition, NO and its derivatives also play critical roles in both the production and reduction of nociception and pain, which is the primary cause of functional disability in OA. These studies suggest that NO donors could be an asset in the treatment of OA.

This article briefly reviews the literature describing a catabolic role for NO in cartilage and chondrocytes, and then summarizes existing studies that may suggest alternative roles for NO in the joint.

NO is synthesized in mammalian cells by the conversion of L -arginine to L -citrulline plus NO. This reaction is catalyzed by one of three isoforms of nitric oxide synthase NOS.

Two of the NOS enzymes, namely endothelial NOS and neuronal NOS, are calcium dependent and constitutively produce relatively low levels of NO.

The inducible isoform inducible NOS [iNOS] is expressed for a longer period of time upon activation by a variety of factors, including the inflammatory cytokines TNF-α and lipopolysaccharide reviewed by Weinberg and coworkers [ 9 ]. Once synthesized, NO can diffuse within the same cell or neighboring cells, where it binds to the heme group of soluble guanylyl cyclase to generate cGMP from GTP [ 10 ].

Activated cGMP then binds specifically to target proteins including transcription factors, protein kinases and phosphodiesterases to elicit downstream effects. However, NO can also act in a cGMP-independent manner, for example by directly modifying proteins or contributing to the oxidation of proteins and lipids, further increasing the complexity and number of potential roles for NO in normal and pathophysiologic functions [ 11 ].

In addition to signaling by the NO molecule alone, ROS including superoxide, hydrogen peroxide, and peroxynitrite are also involved in mediating cellular functions. It is clear that these molecules also have specific cellular functions and play specific roles in pathogenesis.

Peroxynitrite is generated by the combination of NO and superoxide, and it contributes to a number of destructive events in cartilage, including apoptosis [ 12 , 13 ].

Joint fluid analysis in patients with OA identified significantly lower concentrations of the superoxide scavenger enzyme extracellular superoxide dismutase SOD , suggesting an increase in oxidative damage may contribute to damage caused by OA [ 14 ].

Like NO, however, studies have suggested that the role of reactive nitrogen oxide species RNOS in the cell is complex, and newly discovered functions are still being described in the literature. Although this review focuses primarily on the role played by NO and its redox derivatives in the pathogenesis of OA, NO is also involved in normal development.

For example, experiments in chick growth plate chondrocytes illustrated that all three isoforms of NOS are expressed and active in the growth plate Figure 1 [ 15 ], and we have detected both endothelial NOS and neuronal NOS mRNA in chondrocytes of patients with OA [ 16 ].

NO donors increased alkaline phosphatase activity, and transfection of the endothelial NOS isoform increased collagen type X expression. Conversely, incubation with NOS inhibitors reversed the increase in alkaline phosphatase activity, whereas cGMP inhibitors reversed the increases in alkaline phosphatase activity and collagen expression, demonstrating that NO helps to mediate the terminal differentiation of chondrocytes.

These experiments show that NO helps regulate two steps in chondrocyte development, namely expression of collagen type X as well as alkaline phosphatase activity [ 15 ], illustrating just one example of a nonpathological role for NO. Expression patterns of NOS enzymes in chick growth plate chondrocytes.

Longitudinal sections through 8-week-old proximal tibia were immunostained with the antibodies listed and counterstained with Alcian Blue. The upper panels represent the proliferative zone and lower ones the hypertrophic region of the growth plate.

a, b Control section, c, d eNOS, e, f nNOS note that the arrow indicates positively stained hypertrophic chondrocytes , g, h iNOS, i, j anti-nitrocysteine, k, l anti-nitrotyrosine arrow points to an accumulation of nitrosylated and nitrated products.

eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; nNOS, neuronal nitric oxide synthase.

Reproduced with permission from Teixeira and coworkers [ 15 ]. As mentioned in the Introduction section above , there are numerous examples of the catabolic effects of NO on cultured chondrocytes and cartilage.

Chondrocytes from patients with OA express iNOS in the superficial zone [ 16 , 17 ], reflecting an increase in NO during the OA disease process.

NO also inhibits the synthesis of both proteoglycans and collagen in rabbit cartilage cultures [ 18 ] and has been shown to upregulate the synthesis of matrix metalloproteinases in a cGMP-dependent manner [ 19 , 20 ]; both of these actions contribute to destruction of the extracellular matrix.

In addition, NO mediates the expression of proinflammatory cytokines, including IL, and the synthesis of the ILconverting enzyme, a caspase required for the maturation of both IL-1 and IL [ 21 ]. These findings support the conclusion that NO is primarily a catabolic factor in OA.

However, not all chondrocytes respond identically to pro-inflammatory stimuli, and neither do all chondrocytes produce equivalent amounts of NO when they are exposed to the same stimulus. This suggests that a straightforward catabolic role for NO in the joint may be too simplistic.

Häuselmann and colleagues [ 22 ] harvested chondrocytes from different zones of articular cartilage and observed that different layers of cartilage generated varying amounts of NO in response to IL-1 stimulation.

Specifically, chondrocytes from the superficial layer of normal human cartilage synthesized two to three times as much NO as did those from the deep zone of the same cartilage sample. IL-1 stimulation inhibited proteoglycan synthesis equally in both zones.

However, in the presence of the NOS inhibitor N G -monomethyl- L -arginine L -NMA , the ILinduced inhibition of proteoglycan synthesis was completely reversed in the deep zone whereas only a partial effect was observed in the superficial zone. In addition, exposure to L -NMA and IL-1 together reduced the metabolic half-life of proteoglycans in the deep and superficial zones, despite the differing effects on proteoglycan inhibition.

Finally, the authors observed that NO production in response to IL-1 stimulation declined with age. These findings led the authors to suggest that NO may not mediate extracellular matrix turnover identically throughout articular cartilage and, perhaps, plays a protective role in proteoglycan catabolism [ 22 ].

Intriguingly, chondrocytes not only respond differently to NO based on their location in the cartilage, but different effects on cartilage can be elicited depending on the method used to inhibit inflammation. Bezerra and coworkers [ 23 ] examined the effects of NO and peroxynitrite in zymosan-induced arthritis, and found that the addition of both NO and peroxynitrite induced inflammation as measured by histopathology and the glycosaminoglycan content of the cartilage.

Furthermore, when a nonselective NOS inhibitor or a selective iNOS inhibitor was added, the synovitis was improved but the glycosaminoglycan loss was enhanced. This indicates that although blocking NO production helps to decrease inflammation, cartilage damage is enhanced.

Finally, when the peroxynitrite scavenger uric acid was added, both the synovitis and glycosaminoglycan loss was ameliorated, suggesting that inhibiting peroxynitrite production may be a more effective target for protecting against inflammation and cartilage loss in this arthritis model [ 23 ].

Again, these experiments, combined with the different behavior associated with chondrocyte location in the joint, suggest that the role played by NO in the joint may be more complicated than previously understood and that more research is needed.

In addition to contributing to the breakdown of the extracellular matrix, NO also mediates apoptosis. Both exogenous and endogenous NO can induce apoptosis via a mitochondria-dependent mechanism [ 24 , 25 ].

Studies demonstrated that incubation of human articular chondrocytes with the NO donor sodium nitroprusside SNP induced events characteristic of apoptosis, including increasing caspase-3 and caspase-7 expression and downregulating Bcl-2 expression [ 25 ].

Further examination of the mechanisms by which SNP induces apoptosis illustrated that SNP induced DNA fragmentation, cytoskeletal remodeling, mitochondrial dysfunction, caspase activation, and cytochrome c release [ 26 ], all of which are hallmarks of apoptosis.

Treatment with a NO scavenger significantly decreased multiple aspects of SNP-induced cell damage [ 26 ], once again demonstrating the pleiotropic effects of NO.

Interestingly, del Carlo and Loeser [ 12 ] found that incubation with NO alone does not induce apoptotic cell death in chondrocytes. In these experiments, incubation of chondrocytes with the NO donors SNP and 3-morpholiosydnonimine SIN-1 , as well as the ROS peroxynitrite, all induced apoptosis.

However, both SNP and SIN-1 also generate ROS and are not considered to be sources of pure NO. Specifically, SIN-1 generates superoxide in addition to NO [ 27 , 28 ], which can then interact with NO to generate peroxynitrite.

In support of this, treatment with either peroxynitrite or superoxide scavengers resulted in protection against apoptosis caused by incubation with SIN-1 but not with SNP.

Intriguingly, incubation with diazeniumdiolates NOC compounds , which are reliable sources of NO, did not cause cell death and the NOC compounds protected against oxidative stress, perhaps by suppressing chondrocyte energy metabolism.

This study demonstrated that both NO and ROS are required to induce apoptosis, suggesting that NO alone may have beneficial effects in chondrocytes [ 12 ]. Other studies on the effect of NO on chondrocyte apoptosis have focused on the role of apoptosis in terminal differentiation, again illustrating a nonpathological role for NO in development.

An increase in inorganic phosphate was shown to induce apoptosis in terminally differentiated epiphyseal chondrocytes [ 29 ]. Subsequent studies demonstrated that inorganic phosphate increased both nitrate and nitrite concentrations, and this increase was attenuated when either NOS activity or phosphate transport was inhibited.

In addition, inorganic phosphate increased caspase-3 activity and decreased the mitochondrial membrane potential, whereas NOS inhibitors maintained mitochondrial function, illustrating that NO mediates phosphate-dependent chondrocyte apoptosis [ 29 ]. ROS have been shown to have deleterious effects on cells and to contribute to chondrocyte death.

Davies and colleagues [ 30 ] demonstrated that OA cartilage has significantly more DNA damage than normal cartilage, and that this damage was mediated by IL-1 and, ultimately, by ROS. Porcine articular cartilage was harvested from normal tissue and compared with cartilage harvested from OA tissue and the number of single-stranded and double-stranded DNA breaks was analyzed.

In cells from healthy cartilage, increasing concentrations of IL-1 correlated with increasing NO concentrations and increasing DNA damage. The increase in DNA damage was attenuated by incubation with the specific iNOS inhibitor W and the superoxide scavenger SOD, suggesting that superoxide may have a role in generating DNA breaks.

It is not clear, however, what effect DNA damage has on OA cells and the disease process. The authors suggested that DNA damage could alter transcription by increasing errors, which could result in dysfunctional proteins, or alternatively by inhibiting the binding of transcription factors to promoter regions [ 30 ].

There is some evidence that the degenerative activity attributed to an increase in NO concentration could be a result of an increase in the concentration of RNOS.

Clancy and coworkers [ 31 ] demonstrated that NO and peroxynitrite have opposing effects on nuclear factor-κB NF-κB activation in chondrocyte cultures. The transcription factor NF-κB is activated rapidly in response to inflammatory stimuli such as IL-1β and TNF-α and upregulates the transcription of a number of genes involved in cartilage degradation including iNOS, matrix metalloproteinases and COX-2, as well as IL-1β and TNF-α.

Inactive NF-κB is sequestered in the cytoplasm by its inhibitor IκB. Upon activation, IκB is phosphorylated and degraded, which allows NF-κB to translocate to the nucleus and bind to its target DNA sequences.

These experiments suggest that NO is not required for immediate activation of NF-κB and suggest that its catabolic activity could be mediated in part through peroxynitrite [ 31 ].

Effects of peroxynitrite and the NO donor SCNEE on IL-1β stimulated NF-κB p65 nuclear translocation. NF-κB, nuclear factor-κB; NO, nitric oxide; PN, peroxynitrite; SCNEE, S -nitrosocysteine ethyl ester. Reproduced with permission from Clancy and coworkers [ 31 ]. Another group analyzed the differential roles of hydrogen peroxide and superoxide in ILinduced NF-κB activation.

Mendes and colleagues [ 32 ] found that IL-1 stimulation resulted in an increase in both hydrogen peroxide and superoxide in bovine articular chondrocytes, although only superoxide was required for NF-κB activation and iNOS expression. This conclusion is supported by the fact that SOD inhibited ILinduced IκB degradation.

Like Clancy and coworkers [ 31 ], this group also found that NO alone inhibits NF-κB activation and iNOS expression [ 33 ], but they suggested that because the concentration of NO immediately after IL-1 stimulation appeared to be quite low, it was unlikely that significant quantities of peroxynitrite were generated.

This led them to suggest that peroxynitrite is not likely to be required for NF-κB activation in chondrocytes. However, these results do not exclude the possibility that peroxynitrite is able to activate NF-κB, merely that it may not be required.

These results clearly demonstrate the difficulty in teasing out the specific roles played by both NO and ROS in order to determine their involvement in ILinduced NF-κB activation.

Peroxynitrite also helps perpetuate the inflammatory process in mesenchymal progenitor cells MPCs , which are used as a model of cartilage and cartilage repair cells. Whiteman and coworkers [ 34 ] used MPCs to investigate the cellular role of peroxynitrite-modified collagen-II, a biomarker discovered in the serum of patients with both OA and rheumatoid arthritis.

The authors showed that the addition of peroxynitrite-modified collagen-II to MPC cultures induced both iNOS expression and cyclo-oxygenase COX -2 synthesis and that specific iNOS and COX-2 inhibitors blocked this synthesis.

Whiteman and coworkers [ 34 ] suggest that this newly identified proinflammatory pathway may be a target for the development of new therapies for the inflamed joint, reiterating the complexity of NO signaling and the need for continuing research to more fully elucidate the role of NO and its derivatives in cellular physiology and pathophysiology.

Although there is experimental evidence to suggest a catabolic function for NO in the joint, there is also evidence that NO and its derivatives may play a protective role in chondrocytes. In addition, NO has beneficial functions in other tissues, and these activities could potentially occur in chondrocytes as well.

Wound healing experiments showed that supplemental L -arginine injected into animals with dorsal wounds significantly increased both wound-breaking strength and collagen deposition compared with animals injected with saline, although there was no change in plasma NO concentration [ 35 ].

NO was also shown to enhance collagen synthesis in human tendon cells in vitro. When cells harvested from the torn edges of tendons from patients undergoing rotating cuff surgery were transfected with an adenovirus containing the gene for iNOS Ad-iNOS or treated with the NO donor S -nitroso- N -acetylpenicillamine SNAP , total protein and collagen synthesis was enhanced, although higher doses did inhibit collagen synthesis [ 36 ].

These findings were supported by a small randomized double-blind clinical trial in which the same group found that application of a patch containing the NO donor glyceryl trinitrate significantly improved outcomes in patients with supraspinatus tendonopathy compared with patients who received placebo [ 37 ].

This illustrates that the benefits of exogenous NO in tendons is not simply an in vitro effect. So et al. Secondly, the transcription factor NF- κ B is known to regulate neutrophil apoptosis as its inhibition leads to increased apoptosis.

A cGMP-dependent mechanism has been proposed to account for the NO-induced downregulation of BNIP3, a dominant proapoptotic Bcl-2 family member in hepatocytes.

Contrasting studies in macrophage cell lines 22 , 29 , 32 suggest that the redox status of the cell may partially determine the effects of NO. Conflicting evidence suggests that RAW Others have found that such protection is observed when cellular thiols are depleted in RAW It has been proposed that in low thiol concentrations, NO actually protects against cell death, whereas it induces death in cells with normal thiol levels.

In the absence of large quantities of scavenger thiols such as glutathione, but in the presence of oxygen, it is possible that NO S -nitrosates critical effector molecules of apoptosis such as caspases, thus preventing their activation and having an inhibitory effect on the proteolytic cascade.

It has been shown by several groups that NO can inhibit a number of apoptotic proteins, including caspase 3 the protease responsible for the initiation of internucleosomal DNA fragmentation , , , , , , caspase 8, , , caspase 9, caspase 1 , and caspases 2, 3, 4, 6 and 7 activation via S-nitrosation.

Inhibition of caspase 3 has been reported to involve two distinct mechanisms in hepatocytes — direct protein S-nitrosation, and another mechanism, which has not yet been elucidated, but is dependent upon cGMP. Studies have shown that apoptosis in neutrophils and macrophages proceeds via activation of caspase protease enzymes, 10 , , part of the classical apoptotic effector cascade.

However, the upstream mechanisms by which exposure to NO causes these enzymes to become activated has not been clarified, although several theories have been suggested.

N 2 O 3 can cause direct DNA damage or inhibit DNA repair enzymes, leading to an increase in the tumour suppressor protein p53, which has been shown to accumulate in NO-treated macrophages and may be the factor responsible for driving them towards apoptosis.

Instead, this group proposed a role for the endoplasmic reticulum stress pathway involving the transcription factors ATF6 and CHOP leading to cytochrome c release Figure 2.

As previously described, the activation status of the survival factor, NF- κ B, has been shown to play a role in regulation of the induction of inflammatory cell apoptosis.

The result of such inhibition would be downregulation of survival factors under the control of this transcription factor, such as the antiapoptotic Bcl-2 family members. Indeed, this has been observed by a number of studies, as exogenous NO downregulates Bcl-2 but upregulates the proapoptotic protein, Bax, in neurons, , and upregulates Bad and Bax, but downregulates Bcl-2 in human colon adenocarcinoma cells.

In nonsmall cell lung cancer cells, it has been shown that NF-κB inhibition leads to apoptosis by increasing mitochondrial permeability, thus allowing release of cytochrome c and subsequent caspase activation see Figure 2.

As S -nitrosothiols readily transnitrosate endogenous cysteine residues, this supports the concept of S -nitrosation of the NF- κ B p50 subunit as the mechanism of inhibition. In addition, the biphasic effects of NO on NF-κB activation reported by Connelly et al.

are mirrored by its effects on the open probability of the mitochondrial permeability transition pore MPTP. Low concentrations of NO donors GEA , SNAP, SIN-1; 1—20 μ M delayed or had no effect on MPTP opening, while at higher concentrations 20— μ M , opening was enhanced.

Albina et al. In contrast, others have reported that NO inhibits mitochondrial respiration through two distinct pathways. NO has a biphasic effect on apoptosis in many cell types, in which low concentrations delay but higher concentrations enhance this form of cell death, a pattern that has recently been confirmed in neutrophils.

This correlates with the dichotomous action of NO on the activity of caspase enzymes responsible for the execution of apoptosis in vitro. Inhibition of caspases by S-nitrosation is a direct consequence of exposure to low concentrations of NO or, more likely, its oxidation products e. On the other hand, activation of these enzymes observed during the proapoptotic actions of higher concentrations represents a downstream event following initial effects on DNA or mitochondria, and can therefore be considered an indirect effect of NO.

Although the mechanism of inhibition has not yet been fully investigated, it is likely that cGMP production, NF-κB activation and subsequent expression of survival proteins or S-nitrosation of apoptotic proteins will play a major role.

Inhibition of eosinophil apoptosis has been reported, but only with certain sources of NO that are capable of activating sGC with a consequent rise in cGMP. No such inhibitory effects have yet been demonstrated in monocytes or macrophages, and it remains to be seen whether these cell types are capable of producing such a response to low concentrations of NO.

It has been demonstrated that exogenous NO can induce apoptosis in all inflammatory cell types discussed in this review: monocytes, monocyte-derived macrophages, neutrophils and eosinophils. In addition, endogenous NO from iNOS also promotes apoptosis in macrophages.

There still remains some controversy over the mechanism by which this molecule causes this form of cell death, although it involves activation of caspase proteases, and most agree that this occurs through a cGMP-independent pathway.

Moreover, mitochondria appear to play a key role in the initiation of apoptosis by NO through release of cytochrome c , resulting in caspase activation. Modulation of the activation status of the transcription factor NF-κB has also been proposed to account for NO-induced apoptosis in neutrophils and macrophages, and there is an increasing body of evidence to support this theory.

Differences may exist in the mechanisms by which NO causes apoptosis in different cell types that could potentially be exploited to target a particular inflammatory cell type in certain conditions.

Despite the uncertainties and controversies surrounding the regulation of inflammatory cell apoptosis by NO, it is clear that the class and concentration of NO-donating compound used and the cell type are critical determinants of the response.

Major differences between different classes of NO donors and opposing effects with low and high concentrations of certain NO donors are observed. Thus, the amount and rate of NO release and the redox status of the target cell appear to be key factors in the cellular response to NO exposure, and certain NO donors appear to be more effective than others in promoting inflammatory cell apoptosis.

It is also important to realise that the concentration of NO donor used may not necessarily reflect the concentration of NO to which the cells are exposed.

Culture conditions may also affect NO levels; for example, plasma proteins such as albumin are able to scavenge NO through the formation of S -nitrosothiols.

The vast majority of work on this subject has been carried out using in vitro systems, often utilising animal cell lines.

How the results obtained in these systems relate to the in vivo situation during inflammation in humans still largely remains to be determined, but two studies in rabbits show that NO is a promising candidate for treatment or prevention of inflammatory conditions such as atherosclerosis and restenosis, possibly by influencing apoptosis.

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