Abstract Objective. CAS Nitric oxide and joint health Google Scholar Rossoni G, Muscara Kxide, Cirino Oxidde, Wallace JL: Inhibition of cyclo-oxygenase-2 exacerbates ischaemia-induced acute myocardial dysfunction in the rabbit. White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A: Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. ACS Chem.

Nitric oxide and joint health -

Expression of iNOS has been identified in many human cell types, but chondrocytes were among the first to be recognized [ 23 ]. Many additional pieces of evidence link NO to the pathogenesis of osteoarthritis.

Osteoarthritic joints exhibit elevated NO production as well as increased amounts of other inflammatory mediators. Patients with osteoarthritis and rheumatoid arthritis exhibit markers of enhanced NO production in their synovial fluid, serum, and urine, including increased levels of NO, increased circulating nitrites and nitrates, and upregulation of iNOS expression in chondrocytes [ 24 ].

Most human cells that are capable of iNOS expression require multiple synergistically active cytokines to induce NO synthesis.

Human chondrocytes, however, differ significantly and may be induced by a single cytokine such as IL-1 [ 25 ]. iNOS expression in osteoarthritis occurs mainly in chondrocytes, whereas in rheumatoid arthritis it occurs predominantly in synovial lining cells, endothelial cells, chondrocytes, infiltrating mononuclear cells, and synovial fibroblasts [ 25 , 26 ].

Constitutive isoforms of NO synthase are also observed in synovial lining and vascular smooth muscle from osteoarthritic joints [ 27 ]. Much of the in vitro work on the effects of NO has been carried out in environments with normal oxygen tension, whereas cartilage is an avascular tissue with low oxygen tension.

Caution may therefore be needed in extrapolating the results in vivo. Within the context of osteoarthritis, NO appears mostly to be a proinflammatory and destructive mediator.

However, NO is also a mediator of normal physiological responses in the body and is produced by chondrocytes from normal cartilage. Therefore, NO generated by constitutive NOS enzymes may have beneficial effects such as improved blood flow through vasodilatation, but under different circumstances, at higher concentrations produced by iNOS, NO may enhance chondrocyte death and suppress the synthesis of the cartilaginous matrix.

One important factor may be the NO concentration within the microenvironment of the cartilage. Constitutive NOS enzymes generate NO at the picomolar level, whereas iNOS is several orders of magnitude more active. At higher concentrations the effects of NO are mediated through reactive oxygen species, which modulate protein activity through S -nitrosylation of their cysteine residues.

Proteins thus affected include transcription factors, transforming growth factor-β, insulin-like growth factor-I, signaling kinases, ion channels, and matrix metallo-proteinases.

Higher NO concentrations also lead to the formation of peroxynitrite, a reactive mediator formed by the reaction of superoxide with NO, which may have diverse negative effects on protein and cell function [ 28 ].

NO may therefore have a mixture of positive and negative effects in relation to inflammation in osteoarthritic joints. Joint pain is the main symptom of osteoarthritis, and relief of pain is the mainstay of current therapies.

Pain fibers are present throughout all parts of synovial joints except articular cartilage, although in advanced osteoarthritis the articular cartilage becomes partially innervated and vascularized.

The earliest pathological changes in osteoarthritic joints are probably subclinical [ 29 ], but there is also much variability in the symptoms associated with more advanced changes in arthritic joints between patients, in different joints in the same patient, and in individual joints over time.

The role of NO in pain is complex because it is thought to have both positive and negative effects on pain perception. Low level production of NO by the constitutive forms of NOS may relieve pain by increasing vasodilatation and improving circulation as well as by reducing nerve irritation and inflammation per se.

There is some evidence that this pathway of NO production is disrupted in abnormally loaded joints [ 30 ]. Conversely, increased NO production after activation of iNOS by inflammatory cytokines can increase pain perception.

In rat models, it has been shown that it is possible to reduce pain in a vascular pain model by infusing N G -nitro- L -arginine methyl ester L -NAME , an inhibitor of NOS, and to restore the pain by infusing the NO donor sodium nitroprusside, suggesting that the pain is mediated by NO [ 31 ].

Similarly, in another study [ 32 ] infusion of L -NAME prevented hyperalgesia induced by peroxynitrite. In osteoarthritic joints, NO could conceivably reduce pain by several different mechanisms [ 33 ].

Improved blood flow secondary to vasodilatation may restore oxygen, growth factors, and nutrients to the synovium and subchondral bone. Nerve ischemia, leading to abnormal nerve membrane potential and conduction, is also improved by vasodilatation.

Through the cGMP pathway, NO opens potassium channels and reduces calcium influx from calcium channels. Consequent hyperpolarization of the nerve-cell membrane blocks pain transmission. Further studies in humans are needed if we are to understand better the therapeutic possibilities of NO donation in the management of joint pain.

NSAIDs work by blocking prostaglandin synthesis, largely by inhibiting the cyclo-oxygenase COX enzymes, which catalyze the conversion of arachidonic acid to prostaglandins and thromboxane. COX inhibition has anti-inflammatory, analgesic, and antipyretic effects.

There are two main isoforms of the COX enzyme: COX-1 and COX The former is constitutively expressed in most body cells and is thought to have homeostatic functions in tissue maintenance, whereas COX-2 is inducible, being activated by cytokines released from inflammatory cells, such as tumor necrosis factor-α and IL-1, and leads to the production of inflammatory mediator prostaglandins.

Most of the desired effects of NSAIDs for example, their anti-inflammatory effects therefore occur via COX-2 inhibition, whereas the unwanted adverse effects such as gastrointestinal damage largely occur via COX-1 inhibition, especially inhibition of production of the gastric mucosal protectant prostaglandins PGI 2 and PGE 2.

The COX-2 selective inhibitors were designed to have similar anti-inflammatory and analgesic properties to the nonselective NSAIDs but with a lower incidence of gastrointestinal adverse effects such as bleeding and ulcer disease.

Indeed, this has proved to be the case in meta-analyses of clinical trials of COX-2 selective inhibitors versus nonselective NSAIDs [ 34 , 35 ]. When it was first noted that increased cardiovascular risk may be associated with rofecoxib, one proposed mechanism was that COX-2 inhibitors may cause an imbalance of prothrombotic and antithrombotic prostaglandins favoring thrombosis, because COX-2 inhibitors reduce production of prostacyclin by the endothelium, but they do not affect the COX-1 dependent production of thromboxane by platelets.

However, more recent data suggest that although rofecoxib is probably associated with a greater risk for cardiovascular disease than other NSAIDs, the other COX-2 inhibitors probably have a similar risk to that of most of the traditional NSAIDs.

Other mechanisms not specific to COX-2 inhibitors are therefore likely to be important. For example, a recent study showed that both COX-2 inhibitors and traditional NSAIDs upregulate vascular NADPH nicotinamide adenine dinucleotide phosphate oxidases and uncouple eNOS, leading to endothelial dysfunction [ 36 ].

Further clinical studies are ongoing to establish the extent of cardiovascular disease associated with both COX-2 inhibitors and traditional NSAIDs. Early atherosclerotic lesions are thought to be partly influenced by flow patterns and forces exerted on the vessel walls.

In animal models, steady laminar shear stress induces the upregulation of both eNOS and COX-2 [ 37 ]. NO produced by the vascular endothelium is thought to have an important influence on vascular tone and hence blood pressure. Indeed, intravenous infusion of the NO synthase inhibitor N G -monomethyl- L -arginine L-NMMA , increases blood pressure in human volunteers [ 38 ].

Strategies to donate NO may therefore help to lower blood pressure. One example of a drug in which this strategy has been employed is theβ-blocker nebivolol. In addition to its β 1 -receptor antagonist properties, nebivolol also activates eNOS and may stimulate the expression of eNOS, leading to increased NO production.

Although nebivolol has effects on blood pressure similar to those of other β-blockers for instance, atenolol [ 39 ] , it has different hemodynamic effects. For example, unlike atenolol, it causes vasodilatation in the human forearm when it is infused intra-arterially, and this effect can be blocked by the co-administration of L -NMMA, which suggests that it is NO dependent [ 40 ].

Nebivolol also improves endothelial function in hypertensive patients [ 41 ] and reduces arterial wave reflection, thus lowering central blood pressure more than atenolol [ 42 , 43 ]. Even small differences in blood pressure can have major influences on outcome. NSAIDs have variable effects on blood pressure, but several of them appear to increase blood pressure, especially in previously hypertensive individuals.

This effect is thought to occur via different mechanisms, including activation of the renin-angiotensin system, vasoconstriction due to inhibition of vasodilatory prostaglandins, sodium and water retention, and production of vasoconstricting factors including endothelin-1 and metabolites of arachidonic acid.

NSAIDs also interact with antihypertensive medications, counteracting their antihypertensive effects [ 46 ]. In general, treatment with a NSAID or paracetamol tends to cause a small but significant increase in blood pressure.

In one meta-analysis of largely hypertensive patients [ 47 ], indomethacin and naproxen were associated with the greatest increases in blood pressure, whereas ibuprofen, piroxicam, sulindac, and aspirin had negligible effects on blood pressure.

However, in a recent randomized controlled trial [ 48 ], treatment with lumiracoxib led to significantly lower blood pressure than treatment with ibuprofen in patients with controlled hypertension. Overall, both traditional NSAIDs and COX-2 selective NSAIDs appear to increase blood pressure, but there are variations between individual agents.

However, much of the elevation in blood pressure associated with coxibs as a group in this analysis might have been attributable to the effects of rofecoxib.

In a further study [ 50 ], rofecoxib caused increases in systolic and diastolic blood pressures compared with celecoxib. It was hypothesized that this may be due to competition between rofecoxib and aldosterone for metabolism by cytosol reductase; however, aldosterone levels were similar in both arms of the study.

Interestingly, in patients with hypertension and osteoarthritis, patients taking β-blockers or angiotensin-converting enzyme inhibitors had a greater increase in blood pressure and a higher incidence of peripheral edema with rofecoxib than with celecoxib, but there were no significant differences in blood pressure with either coxib in patients taking calcium channel blockers or diuretics [ 51 ].

In another study [ 52 ], among elderly patients with essential hypertension and arthritis, indomethacin increased blood pressure in those taking enalapril but not in those taking amlodipine.

However, in patients taking lisinopril for hypertension, celecoxib had no effect on hour ambulatory blood pressure compared with placebo, with the placebo-corrected differences in hour ambulatory blood pressure being 1. More data are needed on the effects of different NSAIDs on blood pressure and on relationships with pharmacodynamics, pharmacokinetics, and dosing regimens of the various NSAIDs and background antihypertensive therapies.

Based on the data reported so far, it appears that chronic NSAID therapy can influence blood pressure significantly and that this may be relevant to cardiovascular event outcomes. The vascular endothelium is a complex structure that releases mediators with important paracrine and autocrine effects on vascular tone and blood pressure, platelet aggregation, thrombus formation, and atheroma development.

NO is one of many mediators released by the endothelium; others include prostaglandins for example, PGI 2 and PGH 2 , endothelin-1, thromboxane A 2 , interleukins, bradykinin, angiotensin II, chemokines, nuclear factor-κB, and vascular endothelial growth factor Figure 2.

NO availability has long been used to define endothelial function and a reduction in NO bioavailability is generally classed as 'endothelial dysfunction' although in practice, alterations in other mediators may also be involved in this state. Vascular endothelial mediators and their effects.

Adapted with permission from Lüscher and Barton [ ]. Endothelial dysfunction is present in many disease states, including diabetes mellitus [ 54 ], hyperlipidemia [ 55 ], and hypertension [ 56 ], as well as in cigarette smoking [ 57 ] and increasing age [ 58 ]. Interestingly, most of these conditions are considered to be risk factors for cardiovascular disease in their own right, and many of them tend to cluster together in the same individuals.

Indeed, endothelial dysfunction is a good surrogate marker or predictor of cardiovascular risk [ 59 — 61 ] and it is considered by some to be the earliest detectable sign of atherosclerosis [ 62 , 63 ]. More recently, endothelial dysfunction has also been identified in inflammatory arthritides, including rheumatoid arthritis [ 64 — 66 ], systemic lupus erythematosus [ 67 , 68 ], psoriatic arthritis [ 69 ], and ankylosing spondylitis [ 70 ].

In psoriatic arthritis, the degree of endothelial dysfunction has been shown to correlate with disease activity, as assessed using C-reactive protein CRP level and erythrocyte sedimentation rate [ 69 ]. In an anterior-cruciate ligament deficient rabbit knee model of osteoarthritis, there was reduced vascular responsiveness to acetylcholine in the medial collateral ligament vessels compared with controls, suggesting that a degree of endothelial dysfunction may also exist in osteoarthritis [ 71 ], although there is little evidence of this in humans to date.

Several different cardiovascular agents have been shown to improve endothelial function; interestingly, many of these have also improved survival or reduced future cardiovascular events in large outcome trials.

For example, statins improve endothelial function [ 72 ] and reduce mortality [ 73 ]. Also, spironolactone improves endothelial function [ 74 ] and reduces mortality in patients with heart failure [ 75 ].

Other examples include aspirin [ 76 ] and angiotensin converting enzyme inhibitors [ 77 ]. In most cardiovascular studies nitrates have not affected survival outcomes, but there are exceptions. When combined, isosorbide dinitrate and hydralazine therapy given to African-Americans with heart failure improved survival significantly compared with placebo [ 78 ].

Hydralazine has antioxidant effects in addition to its blood pressure lowering effects [ 79 ], and it has been suggested that this may partly account for the favorable outcome in the above study.

However, it is also of note that a meta-analysis [ 80 ] showed that long-term organic nitrate use in patients after myocardial infarction was associated with higher mortality. Therefore, it is not possible at present to generalize about whether NO donors and drugs improving endothelial function will always improve outcome, because further investigation of the effects of individual agents is required.

There are many ways to measure endothelial function. The 'gold standard' method employs venous occlusion plethysmography to measure forearm blood flow responses to intrabrachial arterial infusions of the endothelium-dependent vasodilator acetylcholine [ 81 ].

Usually, the NO-releasing endothelium-independent vasodilator sodium nitroprusside is infused as a control, and baseline production of NO by the endothelium can also be assessed by measuring the reduction in forearm blood flow after infusion of the NOS inhibitor L -NMMA.

Endothelial function can also be measured in the coronary arteries, for example during coronary angiography, again by assessing vascular responses to infusion of acetylcholine.

Other less invasive methods of assessing endothelial function include flow-mediated dilatation [ 82 , 83 ], which involves measuring flow responses to brief cuff occlusion of the brachial artery using ultrasonography, and using pulse wave analysis to measure responses to the endothelium-dependent vasodilator salbutamol in comparison with the endothelium-independent vasodilator GTN [ 84 ].

Plasma or serum markers of endothelial function, including N -acetyl-β-glucosaminidase, E-selectin, P-selectin, and intracytoplasmic adhesion molecule-1, and the presence of circulating endothelial progenitor cells have also been used to assess endothelial activity.

In several studies it has been shown that aspirin improves endothelial function in humans [ 76 , 85 , 86 ], and this is one of the mechanisms that has been proposed for its cardiovascular protective effect.

However, data regarding the effects of other NSAIDs on endothelial function are less clear. In one study, diclofenac infusion increased methacholine-induced vasodilatation measured by venous occlusion plethysmography only in those with chronic renal failure, but not in healthy volunteers [ 87 ].

In patients with rheumatoid arthritis, neither indomethacin nor rofecoxib improved flow-mediated dilatation [ 88 ]. Likewise, 8 weeks of rofecoxib therapy in patients with coronary artery disease had no influence on flow-mediated dilatation or inflammatory markers [ 89 ], but in two other studies short-term [ 90 ] or 6 months of therapy [ 91 ] with rofecoxib led to reductions in CRP and IL-6 levels but no changes in brachial artery flow-mediated dilatation.

In another study [ 92 ], no change in acetylcholine-induced forearm blood flow response was seen after treatment with either rofecoxib or naproxen in healthy volunteers. Hence, many of the data have suggested little effect of these drugs on endothelial function. Interestingly, however, parecoxib prodrug of valdecoxib reduced endothelium-dependent vasodilatation in response to acetylcholine measured using venous occlusion plethysmography in patients with essential hypertension [ 93 ].

Conversely, in a crossover study of male patients with severe coronary artery disease, 2 weeks of celecoxib therapy resulted in greater brachial artery flow-mediated endothelium-dependent dilatation compared with placebo.

Celecoxib therapy also reduced high-sensitivity CRP and oxidized low-density lipoprotein levels [ 94 ], suggesting that it had a positive effect on reducing inflammation and oxidative stress, although whether this was the mechanism for the improvement in endothelial function is not clear.

Celecoxib has also been found to improve flow-mediated dilatation in patients with essential hypertension both acutely and after 1 week of therapy [ 95 ]. Whether differing effects of NSAIDs on endothelial function are directly relevant to the overall cardiovascular risks attributable to each agent remains to be determined [ 61 ].

Aspirin inhibits platelet aggregation by binding irreversibly to platelet COX-1, inhibiting the production of platelet thromboxane for the life of the platelet. Other nonselective NSAIDs bind reversibly to COX-1 and have variable degrees of antiplatelet aggregatory effects, depending on the degree of COX-1 inhibition and the affinity of binding.

In addition, some NSAIDs appear to interfere with the ability of aspirin to bind to platelet COX-1 and may therefore inhibit the antiplatelet effects of aspirin in patients taking both together.

This may even negate the influence of low-dose aspirin in cardiovascular disease prevention. In a recent study measuring ex vivo platelet function in healthy volunteers [ 96 ], ibuprofen, naproxen, indomethacin, and tiaprofenic acid were found to reduce the effect of aspirin on platelets.

No apparent interaction with platelet function was observed between celecoxib or sulindac and aspirin. Studies have also suggested a link between co-administration of ibuprofen and aspirin and reduced cardiovascular disease prevention with aspirin [ 97 , 98 ]. NO inhibits platelet aggregation via a cGMP-dependent mechanism, and therefore the co-administration of NO with NSAIDs could be beneficial in some circumstances in which inhibition of platelet aggregation is also a goal in a patient who requires NSAID therapy.

Over the past few years, 'NO-releasing' NSAIDs have been developed; in these agents, an NSAID is chemically linked with a NO moiety [ 99 ]. Originally, these were designed to improve the gastrointestinal side-effect profiles of the NSAIDs; in particular, it was hoped that they would reduce ulcer disease and gastrointestinal hemorrhage.

However, as more evidence accumulates about the possible adverse cardiovascular effects of many of the NSAIDs, the question of whether the addition of the NO moiety to a NSAID might improve the cardiovascular risk profile of patients taking chronic NSAIDs has arisen.

NO is released slowly from the CINOD, and this is thought to take place in vivo via an enzymatic esterase based reaction [ ]. Various CINODs have been developed, including NO derivatives of aspirin, flurbiprofen, naproxen naproxcinod , diclofenac, and ibuprofen.

Few data are currently available on their effects in humans. CINODs have extra effects over and above those of their parent NSAID. For example, NO-aspirin, unlike standard aspirin, reduces levels of the proinflammatory cytokine IL-1β by inhibiting gastric caspase-1 activity [ ].

In various animal models of acute and chronic inflammation, CINODs have exhibited similar or even greater effects on inhibition of inflammation to those of their parent NSAIDs [ , ]. Also, a NO-releasing aspirin derivative had a sevenfold more potent effect on inhibition of platelet aggregation than aspirin when given to rats [ ].

Data on the vascular effects of CINODs show that there is some influence on vascular tone. In vitro , the CINODs NO-flurbiprofen and NO-aspirin, and a NO-steroidal compound, NO-prednisolone, all cause vasorelaxation of rat aortic rings via a NO-dependent mechanism, with a vasodilator potency at least three orders of magnitude less than that of sodium nitroprusside [ ].

However, there were no effects on systemic blood pressure when NO-flurbiprofen or NO-aspirin were given intravenously to anesthetized rats. When naproxen or naproxcinod was administered to rats for 4 weeks, the naproxen treated rats had significantly higher blood pressure than did those treated with naproxcinod or placebo.

In a group of rats pretreated with the NOS inhibitor L -NAME to induce hypertension, naproxcinod reduced the blood pressure significantly whereas naproxen alone increased the blood pressure [ ]. The effects of naproxcinod on blood pressure in humans have been investigated in clinical studies.

A 6-week clinical phase 2 study conducted in osteoarthritis patients comparing naproxcinod versus rofecoxib and naproxen [ ] showed trends toward reductions in mean systolic and diastolic blood pressures with naproxcinod mg and mg twice daily, as compared with trends towards increased blood pressure in the rofecoxib and naproxen mg groups.

The first phase 3 study with naproxcinod in patients with osteoarthritis [ ] identified small reductions from baseline in mean office systolic blood pressure with naproxcinod mg twice daily and in mean office diastolic blood pressure with naproxcinod mg twice daily or mg twice daily, as compared with naproxen mg twice daily.

In an exploratory hour ambulatory blood pressure monitoring study performed in hypertensive patients [ ], differential effects on blood pressure of naproxcinod compared with naproxen were also observed.

Although the primary end-point of least square mean change from baseline in average hour systolic blood pressure 1.

Some of the human data presented thus far reveal non-significant trends rather than actual differences in blood pressure.

However, even small reductions in blood pressure may have significant effects on cardiovascular outcome within the context of chronic therapy with NSAIDs, because it has been reported that use of many of these agents including naproxen, meloxicam, diclofenac, and ibuprofen results in average increases in mean arterial pressure as high as 5.

Further data are required to evaluate whether there is a true benefit of CINODs on blood pressure in humans, and such studies are currently ongoing. The effects of CINODs on endothelial function are not yet known.

Also, it is unclear whether CINODs might be subject to the development of vascular tolerance in a similar way to that seen with organic nitrates. Using left ventricular end-diastolic pressure as a surrogate marker for myocardial dysfunction in an in vitro perfused rabbit heart model [ ], pretreatment with aspirin, celecoxib, or meloxicam increased myocardial damage after ischemic insult and reperfusion.

However, pretreatment with NCX an NO-releasing aspirin derivative had the opposite effect, reducing myocardial damage and dysfunction caused by the insult. It is potentially the case that some of the cardiovascular risk associated with chronic NSAID use may be ameliorated by steady donation of NO in the vasculature.

However, further work in humans is necessary to investigate this potential. Osteoarthritis is a common and disabling disease that is becoming more prevalent as our population ages.

Partly as a result of its association with increased age, many patients being treated for osteoarthritis will also have risk factors for cardiovascular disease. Therefore, the remit of future treatment strategies for osteoarthritis must broaden from simply managing joint pain to take into account the overall management of the patient as well, along with any co-existing risk factors.

We must also carefully consider the risks for gastrointestinal, cardiovascular, and other adverse effects of all drug therapies.

Both traditional NSAIDs and COX-2 selective NSAIDs have been associated with increased cardiovascular risk, but many patients with osteoarthritis rely on these medications to achieve adequate symptomatic control; therefore, any measures that might counteract the cardiovascular risks associated with NSAIDs would be welcome.

NO is a key regulator of vascular function in health and disease with effects on vascular tone, platelet function, and endothelial function. The donation of extra NO by pharmaceutical agents is a possible means of influencing vascular function and cardiovascular outcomes.

The recently developed CINODs represent an exciting new class of agent that show promise in the pharmacological management of the pain associated with osteoarthritis, being at least as effective as NSAIDs in animal studies to date.

They have also shown some potential for being more effective, given the effects of NO on pain perception, while also offering additional benefits such as increased gastric protection. This may improve pain control in osteoarthritis. At the same time, previous data have suggested that some of the joint damage in osteoarthritis has been mediated by NO; this therefore requires further investigation in humans.

However, turning once again to the broader cardiovascular perspective, there may be some overall advantages of these compounds in the management of osteoarthritis.

Theoretically, CINODs may influence endothelial function, vascular tone, and other surrogate markers of cardiovascular risk.

If this were shown to reduce the incidence of cardiovascular events in patients taking chronic NSAID therapy, then this would be a major breakthrough in the management of arthritis in general.

Further studies to investigate the effects of CINODs on blood pressure, vascular function, and structure will guide their future use in humans. National Collaborating Centre for Chronic Conditions: Osteoarthritis: National Clinical Guidelines for Care and Management in Adults.

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Download references. You can also search for this author in PubMed Google Scholar. Department of Physiology and Medicine, LSU Medical Center, Pardido Street, , New Orleans, LA, USA.

Department of Immunology, Berlex Biosciences, Inc. Reprints and permissions. Evans, C. In: Lancaster, J. eds Nitric Oxide, Cytochromes P, and Sexual Steroid Hormones. Ernst Schering Research Foundation Workshop, vol Springer, Berlin, Heidelberg. Publisher Name : Springer, Berlin, Heidelberg.

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Policies and ethics. Skip to main content. Abstract Arthritis is a disease of diarthrodial joints. Keywords Nitric Oxide Articular Cartilage Synovial Fluid Nitric Oxide Production Articular Chondrocytes These keywords were added by machine and not by the authors.

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Th 17 cells have been identified as cells induced by IL-6 and TGF-β and expanded by IL [ 65 ]. Similarly to Th 1 and Th 2 subsets, Th 17 development relies on the action of a lineage-specific transcription factor. Th 17 cells have emerged as an independent subset because their differentiation was independent of the Th 1 and Th 2 promoting transcription factors T-bet, STAT1, STAT4 and STAT6.

ROR-γt, RORα and STAT3 appear to be critical for the development of Th 17 cells. Th 17 cells produce IL and are thought to clear extracellular pathogens that are not effectively handled by either Th 1 or Th 2 cells, and have also been strongly implicated in allergic diseases [ 66 ].

In addition to IL, Th 17 cells produce other proinflammatory cytokines such as IL and IL Increased levels of IL have been observed in patients with RA.

Indeed, IL can directly and indirectly promote cartilage and bone destruction. IL deficient mice develop attenuated collagen-induced arthritis.

The role of NO in IL and TGF-β-induced Th 17 cell differentiation has not been studied yet. Regulatory T cells Tregs represent a subset of T cells involved in peripheral immune tolerance. Tregs seem to have an impaired regulatory function in RA. The existence of human NO-Tregs has not been investigated yet.

Whilst NO plays a central role in many physiological processes, its increased production is pathological. NO mediates many different cell functions at the site of synovial inflammation, including cytokine production, signal transduction, mitochondrial functions and apoptosis Table 1.

The effects of NO depend on its concentration. Increased NO production plays an important role in the pathogenesis of both SLE and RA. Further studies are needed to determine the cellular and molecular mechanisms by which NO regulates immune cell functions.

NOS inhibition may represent a novel therapeutic approach in the treatment of chronic autoimmune diseases. Brown CG: Nitric oxide and mitochondrial respiration. Biochem Biophys Acta. CAS PubMed Google Scholar. Beltrán B, Mathur A, Duchen MR, Erusalimsky JD, Moncada S: The effect of nitric oxide on cell respiration: a key to undertanding its role in cell survival or death.

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Pham TN, Rahman P, Tobin YM, Khraishi MM, Hamilton SF, Alderdice C, Richardson VJ: Elevated serum nitric oxide levels in patients with inflammatory arthritis associated with co-expression of inducible nitric oxide synthase and protein kinase C-eta in peripheral blood monocytederived macrophages.

J Rheumatol. Onur O, Akinci AS, Akbiyik F, Unsal I: Elevated levels of nitrate in rheumatoid arthritis. Rheumatol Int. Choi JW: Nitric oxide production is increased in patients with rheumatoid arthritis but does not correlate with laboratory parameters of disease activity.

Clin Chim Acta. Gonzalez-Gay MA, Llorca J, Sanchez E, Lopez-Nevot MA, Amoli MM, Garcia-Porrua C, Ollier WE, Martin J: Inducible but not endothelial nitric oxide synthase polymorphism is associated with susceptibility to rheumatoid arthritis in northwest Spain. Rheumatology Oxford. Firestein GS, Budd RC, Harris ED, McInnes IB, Ruddy S, Sergent JS: Kelley's Textbook of Rheumatology.

Google Scholar. van't Hof RJ, Ralston SH: Nitric oxide and bone.

Thank you for visiting nature. You are using a browser version with limited support Polyphenols and blood sugar control CSS. To jount the best experience, we anx you use hhealth Nitric oxide and joint health up to date browser or turn Nirtic compatibility mode in Internet Explorer. Nitric oxide and joint health the meantime, to ensure Nitric oxide and joint health support, we are displaying the site without styles and JavaScript. Patients with established rheumatoid arthritis RA and disease modifying treatments have lower nitric oxide NO levels in the alveolar compartment C A NO and in the airway wall C aw NObut also higher diffusion capacities for NO in the airways D aw NO compared to matched controls. The aim of the present study was to investigate the NO lung dynamics in patients with recent onset RA before and after immune suppression with methotrexate therapy. Patients with early RA and antibodies against anticitrullinated peptides ACPA were recruited.

Nitric oxide and joint health -

J Rheumatol ; 21 : —8. Sakurai H, Kohsaka H, Liu M et al. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritis. J Clin Invest ; 96 : — Grabowski PS, Wright PK, van 't Hof RJ, Helfrich MH, Oshima H, Ralston SH.

Immunolocalisation of inducible nitric oxide synthase in the synovium and cartilage in rheumatoid arthritis and osteoarthritis. Br J Rheumatol ; 36 : —5. Firestein GS, Yeo M, Zvaifler NJ. Apoptosis in rheumatoid arthritis synovium.

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Biochem Biophys Res Commun ; : 15 — Wei XQ, Charles IG, Smith A et al. Altered immune response in mice lacking inducible nitric oxide synthase. Nature ; : — Ralston SH, Grabowski PS. Mechanisms of cytokine induced bone resorption: Role of nitric oxide, cyclic guanosine monophosphate, and prostaglandins.

Bone ; 19 : 29 — Firestein GS. Novel therapeutic strategies involving animals, arthritis, and apoptosis. Curr Opin Rheumatol ; 10 : — Morita I, Matsuno H, Sakai K et al. Int J Tissue React ; 20 : 37 — Oxford University Press is a department of the University of Oxford.

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Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Journal Article. Nitric oxide is a mediator of apoptosis in the rheumatoid joint. van't Hof , R. van't Hof.

Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen AB25 2ZD, UK. Oxford Academic.

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Issue 7, From the journal: Biomaterials Science. Nitric oxide scavengers based on o -phenylenediamine for the treatment of rheumatoid arthritis. This article is part of the themed collection: Biomaterials Science 10th Anniversary Collection.

You have access to this article. Please wait while we load your content Something went wrong. Try again? Cited by. Download options Please wait Article type Paper. Submitted 04 Dec Accepted 04 Feb The development of guidelines and protocols for the use of Nitric Oxide donors in clinical practice can facilitate their integration into therapeutic regimens for arthritis.

Understanding the patient-specific factors that can influence the response to Nitric Oxide donors is also crucial. Individual variations in genetics, metabolism, and disease severity can affect the efficacy of Nitric Oxide donors in managing pain.

Personalised approaches to pain management using Nitric Oxide donors can help in optimising therapeutic outcomes for individuals with arthritis. The development and implementation of Nitric Oxide-based therapeutic interventions pose several challenges. The dual role of Nitric Oxide in physiological and pathological processes necessitates a careful consideration of its therapeutic applications.

The balance between the beneficial and detrimental effects of Nitric Oxide is crucial in developing effective and safe therapeutic interventions. The specificity of Nitric Oxide-targeted interventions is also a significant challenge. The diverse roles of Nitric Oxide in various cellular processes require the development of targeted interventions that can modulate Nitric Oxide levels in specific tissues or cells.

The advancement in drug delivery systems and targeted therapies can help in addressing the challenges related to the specificity of Nitric Oxide interventions. The translation of preclinical findings to clinical practice is another challenge in the development of Nitric Oxide-based therapies.

The differences in physiology, metabolism, and disease progression between animal models and humans necessitate rigorous clinical testing and validation of Nitric Oxide interventions.

The conduct of well-designed clinical trials is essential to assess the efficacy, safety, and optimal dosages of Nitric Oxide-based therapies in humans. The exploration of Nitric Oxide in managing joint pain and arthritis is a burgeoning field with immense potential.

Future research endeavours should focus on elucidating the molecular mechanisms underlying the diverse roles of Nitric Oxide in arthritis and joint pain. The identification of novel targets and pathways modulated by Nitric Oxide can pave the way for the development of innovative therapeutic strategies.

The development of novel Nitric Oxide donors, modulators, and inhibitors is crucial in expanding the therapeutic arsenal for managing arthritis and joint pain. The synthesis of novel compounds with enhanced specificity, stability, and bioavailability can improve the therapeutic potential of Nitric Oxide-based interventions.

The exploration of combination therapies involving Nitric Oxide modulators and other therapeutic agents can enhance the efficacy of treatment regimens for arthritis. For more everything you need to know about nitric oxide and the role it plays in the human body, check out our comprehensive information page here.

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Just added to your cart. Continue Shopping. Close search. Home Nitric Oxide The Role of Nitric Oxide in Managing Joint Pain and Arthritis. The Role of Nitric Oxide in Managing Joint Pain and Arthritis by Ron Goedeke.

The Role of Nitric Oxide in Managing Joint Pain and Arthritis Arthritis and joint pain are prevalent conditions that impact millions globally, causing inflammation, pain, and stiffness in the joints. Inducible Nitric Oxide Synthase iNOS and its Regulation Inducible Nitric Oxide Synthase iNOS is a key enzyme responsible for producing Nitric Oxide NO from L-arginine.

Dual Role of Nitric Oxide in Osteoarthritis Osteoarthritis OA is a degenerative disease involving chondrocytes, cartilage, and other joint tissues. Increased Expression of NOS2 in Rheumatoid Arthritis Patients with Rheumatoid Arthritis RA have been observed to have increased NOS activity and increased NOS2 antigen content compared to normal subjects.

Nitric Oxide and Apoptosis in Arthritic Cells Nitric Oxide helps mediate apoptosis in arthritic cells, affecting the progression of arthritis.

Proinflammatory Activation and Nitric Oxide Nitric Oxide can inhibit proinflammatory activation, which has significant implications in managing arthritis.

Nitric Oxide Donors and Pain Management Nitric Oxide donors have shown promise in managing pain associated with arthritis.

Challenges in Therapeutic Intervention of Nitric Oxide The development and implementation of Nitric Oxide-based therapeutic interventions pose several challenges.

Future Research and Potential Therapies involving Nitric Oxide The exploration of Nitric Oxide in managing joint pain and arthritis is a burgeoning field with immense potential. Summary Inducible Nitric Oxide Synthase iNOS and its Regulation iNOS is crucial for producing Nitric Oxide NO from L-arginine.

It plays a pivotal role in immune activation, inflammation, and various pathologies including arthritis. Extensive knowledge about the roles, structure, and regulation of iNOS has been accumulated.

Many potent iNOS inhibitors have shown promise in animal models. Translating results from animal studies to humans remains a challenge; no iNOS inhibitors are approved for human use.

Understanding the dual modalities of iNOS and NO is crucial for therapeutic intervention.

Arthritis Nitric oxide and joint health ooxide pain are prevalent conditions that Nitric oxide and joint health millions hoint, causing inflammation, pain, and Brain-boosting nutrients in the joints. Nitric Oxide NOa versatile player in the physiological xoide pathological processes of the human body, has ixide recognised oxidd a crucial factor in managing these conditions. This article delves into the multifaceted role of Nitric Oxide in arthritis and joint pain, exploring its impact, regulation, and potential therapeutic applications. Inducible Nitric Oxide Synthase iNOS is a key enzyme responsible for producing Nitric Oxide NO from L-arginine. It plays a pivotal role in immune activation and inflammation, being implicated in various pathologies like sepsis, cancer, neurodegeneration, and different types of pain, including arthritis. The regulation, structure, and inhibition of iNOS are crucial in understanding its role in these conditions.

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Nitruc Exp Med Biol oxidde Cannon GW, Remmers EF, Wilder RL, Hibbs JB, Griffiths MM Nitric oxide production during adjuvant-induced arthritis is associated with tumor necrosis factor genotype. Transplant Proc — Cannon GW, Openshaw SJ, Hibbs JB, Hoidal JR, Huecksteadt TP, Griffiths MM Nitric oxide production during adjuvant-induced and collagen-induced arthritis.

Arthritis Rheum — Cao M, Westerhausen-Larson A, Niyibizi C, Kavalkovich K, Georgescu HI, Rizzo CF, Hebda PA, Stefanovic-Racic M, Evans CH Nitric oxide inhibits the synthesis of type II collagen without altering COL2A I mRNA abundance: prolyl hydroxylase as a possible target.

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: Nitric oxide and joint health

Nitric Oxide in Arthritis: It’s Probably There But What’s It Doing? | SpringerLink	In an anterior-cruciate ligament deficient rabbit knee model of osteoarthritis, there was reduced vascular responsiveness to acetylcholine in the medial collateral ligament vessels compared with controls, suggesting that a degree of endothelial dysfunction may also exist in osteoarthritis [ 71 ], although there is little evidence of this in humans to date. This article delves into the multifaceted role of Nitric Oxide in arthritis and joint pain, exploring its impact, regulation, and potential therapeutic applications. Article CAS PubMed Google Scholar Download references. TNF-α treatment decreases TCR ζ chain expression of T cells [ 62 ] in a GSH-precursor-sensitive way, showing the role of redox balance in the regulation of TCR ζ chain expression. Findings to date have had a major influence on the use of these drugs in the management of chronic arthritic conditions, with regulatory authorities advising against the use of these drugs in patients with known cardiovascular disease or who are at high cardiovascular risk. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritis. Kuo, C.
Exhaled nitric oxide in early rheumatoid arthritis and effects of methotrexate treatment	Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Journal Article. Nitric oxide is a mediator of apoptosis in the rheumatoid joint. van't Hof , R. van't Hof. Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen AB25 2ZD, UK. Oxford Academic. Google Scholar. Revision received:. PDF Split View Views. Cite Cite R. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. Close Navbar Search Filter Rheumatology This issue British Society for Rheumatology Journals Rheumatology Books Journals Oxford Academic Enter search term Search. Abstract Objective. Rheumatoid arthritis , Cytokines , Nitric oxide , Apoptosis , Cartilage , Synovium. Open in new tab Download slide. Ann Rheum Dis. Eur J Pharmacol. Arthritis Rheum. J Exp Med. Br J Pharmacol. Biochem Biophys Res Commun. J Immunol. Br J Rheum. J Rheumatol. J Clin Invest. Br J Rheumatol. Clin Exp Rheumatol. J Biol Chem. Am J Pathol. Biochem Mol Biol Int. Curr Opin Rheumatol. Int J Tissue React. Issue Section:. Download all slides. Comments 0. Add comment Close comment form modal. I agree to the terms and conditions. You must accept the terms and conditions. Add comment Cancel. Submit a comment. Comment title. You have entered an invalid code. Submit Cancel. Thank you for submitting a comment on this article. Your comment will be reviewed and published at the journal's discretion. Please check for further notifications by email. Views 2, More metrics information. Total Views 2, Email alerts Article activity alert. Advance article alerts. New issue alert. Subject alert. Receive exclusive offers and updates from Oxford Academic. 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The specificity of Nitric Oxide-targeted interventions is also a significant challenge. The diverse roles of Nitric Oxide in various cellular processes require the development of targeted interventions that can modulate Nitric Oxide levels in specific tissues or cells. The advancement in drug delivery systems and targeted therapies can help in addressing the challenges related to the specificity of Nitric Oxide interventions. The translation of preclinical findings to clinical practice is another challenge in the development of Nitric Oxide-based therapies. The differences in physiology, metabolism, and disease progression between animal models and humans necessitate rigorous clinical testing and validation of Nitric Oxide interventions. The conduct of well-designed clinical trials is essential to assess the efficacy, safety, and optimal dosages of Nitric Oxide-based therapies in humans. The exploration of Nitric Oxide in managing joint pain and arthritis is a burgeoning field with immense potential. Future research endeavours should focus on elucidating the molecular mechanisms underlying the diverse roles of Nitric Oxide in arthritis and joint pain. The identification of novel targets and pathways modulated by Nitric Oxide can pave the way for the development of innovative therapeutic strategies. The development of novel Nitric Oxide donors, modulators, and inhibitors is crucial in expanding the therapeutic arsenal for managing arthritis and joint pain. The synthesis of novel compounds with enhanced specificity, stability, and bioavailability can improve the therapeutic potential of Nitric Oxide-based interventions. The exploration of combination therapies involving Nitric Oxide modulators and other therapeutic agents can enhance the efficacy of treatment regimens for arthritis. For more everything you need to know about nitric oxide and the role it plays in the human body, check out our comprehensive information page here. We've created a Nitric Oxide boosting supplement with a combination of ingredients required by our bodies to produce optimal amounts of nitric oxide. Our supplement comes as an easy to mix, great tasting powder, offering a therapeutic dose in each scoop. Learn more about it here. Ron Goedeke MD, BSc Hons MBChB, FNZCAM. Ron Goedeke, an expert in the domain of functional medicine, dedicates his practice to uncovering the root causes of health issues by focusing on nutrition and supplement-based healing and health optimisation strategies. An esteemed founding member of the New Zealand College of Appearance Medicine, Dr. Goedeke's professional journey has always been aligned with cutting-edge health concepts. Having been actively involved with the American Academy of Anti-Aging Medicine since , he brings over two decades of knowledge and experience in the field of anti-aging medicine, making him an eminent figure in this evolving realm of healthcare. Throughout his career, Dr. Goedeke has been steadfast in his commitment to leverage appropriate nutritional guidance and supplementation to encourage optimal health. This has allowed him to ascend as one of the most trusted authorities in the arena of nutritional medicine in New Zealand. His expertise in the intricate relationship between diet, nutritional supplements, and overall health forms the backbone of his treatment approach, allowing patients to benefit from a balanced and sustainable pathway to improved wellbeing. Just added to your cart. Continue Shopping. Close search. Home Nitric Oxide The Role of Nitric Oxide in Managing Joint Pain and Arthritis. The Role of Nitric Oxide in Managing Joint Pain and Arthritis by Ron Goedeke. The Role of Nitric Oxide in Managing Joint Pain and Arthritis Arthritis and joint pain are prevalent conditions that impact millions globally, causing inflammation, pain, and stiffness in the joints. Inducible Nitric Oxide Synthase iNOS and its Regulation Inducible Nitric Oxide Synthase iNOS is a key enzyme responsible for producing Nitric Oxide NO from L-arginine. Dual Role of Nitric Oxide in Osteoarthritis Osteoarthritis OA is a degenerative disease involving chondrocytes, cartilage, and other joint tissues. Increased Expression of NOS2 in Rheumatoid Arthritis Patients with Rheumatoid Arthritis RA have been observed to have increased NOS activity and increased NOS2 antigen content compared to normal subjects. Nitric Oxide and Apoptosis in Arthritic Cells Nitric Oxide helps mediate apoptosis in arthritic cells, affecting the progression of arthritis. Proinflammatory Activation and Nitric Oxide Nitric Oxide can inhibit proinflammatory activation, which has significant implications in managing arthritis. Nitric Oxide Donors and Pain Management Nitric Oxide donors have shown promise in managing pain associated with arthritis. Challenges in Therapeutic Intervention of Nitric Oxide The development and implementation of Nitric Oxide-based therapeutic interventions pose several challenges. Future Research and Potential Therapies involving Nitric Oxide The exploration of Nitric Oxide in managing joint pain and arthritis is a burgeoning field with immense potential. Summary Inducible Nitric Oxide Synthase iNOS and its Regulation iNOS is crucial for producing Nitric Oxide NO from L-arginine. It plays a pivotal role in immune activation, inflammation, and various pathologies including arthritis. Extensive knowledge about the roles, structure, and regulation of iNOS has been accumulated. Many potent iNOS inhibitors have shown promise in animal models. Translating results from animal studies to humans remains a challenge; no iNOS inhibitors are approved for human use. Understanding the dual modalities of iNOS and NO is crucial for therapeutic intervention. Dual Role of Nitric Oxide in Osteoarthritis NO has both protective and catabolic roles in osteoarthritis. It mediates the inflammatory response and is involved in the degradation of matrix metalloproteinases. Exogenous NO may inhibit proinflammatory activation and stimulate collagen synthesis in some conditions. The protective and opposing activities of NO suggest potential roles in chondrocyte function and pain management in OA. Nitric Oxide and Inflammatory Response in Arthritis NO contributes significantly to articular pain in arthritis. Systemic and local treatment with NOS inhibitors have shown to inhibit articular incapacitation induced by zymosan. NO donors inhibit articular incapacitation, suggesting a dual effect of nitric oxide in articular inflammatory pain.
The Role of Nitric Oxide in Managing Joint Pain and Arthritis | Biosphere Nutrition	The experiment was performed twice, totaling 30 animals Following the same protocol as for Figure 3 , knee joint samples were collected 15 h after MSU injection, and sections were stained with Hematoxylin and Eosin. Arterioscler Thromb Vasc Biol. Provided by the Springer Nature SharedIt content-sharing initiative. Even in these early years it was clear that nitrate therapy was hampered by the development of nitrate tolerance, although the mechanisms for this were not understood and indeed are still being elucidated today [ 8 ]. Those investigators also showed that soluble guanylate cyclase could be activated by NO [ 12 ] and agreed with Murad's theory that NO could be the mediator of the action of nitrovasodilators on vascular smooth muscle. In this study, we proposed a new method to discover effective NO scavengers in the form of small molecules. Search all BMC articles Search.
Top bar navigation	Wright, S. Journals Current Journals Archive Journals All Journals. Noint Am Coll Healtu. Wang B, Ma Preventing diabetes through school health initiatives, Nitric oxide and joint health X, Lipsky Jolnt Triptolide, an active component Nitric oxide and joint health the Chinese herbal remedy Tripterygium wilfordii Hook F, inhibits production of nitric oxide by decreasing inducible nitric oxide synthase gene transcription. Abbreviations eNOS: endothelial NOS GSH: glutathione IFN: interferon IL: interleukin iNOS: inducible NOS IP 3 : inositol-1,4,5-triphosphate MHP: mitochondrial hyperpolarization mTOR: mammalian target of rapamycin nNOS: neuronal NOS NO: nitric oxide NOS: NO synthase RA: rheumatoid arthritis SLE: systemic lupus erythematosus TCR: T cell antigen receptor TGF: transforming growth factor Th: T helper TNF: tumor necrosis factor Treg: regulatory T cell TWHF: Tripterygium wilfordii Hook F.
The Role of Nitric Oxide in Managing Joint Pain and Arthritis	Expert Rev. Online ISBN : However, much of the elevation in blood pressure associated with coxibs as a group in this analysis might have been attributable to the effects of rofecoxib. Medicine and Health. Not only in gout arthritis, but in most inflammatory disease, NF-κB regulates the transcription of varied inflammatory molecules Pahl, ; Tak and Firestein, Curr Opin Rheumatol.

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