Gouty Inflammation Research Articles

Rapid CCL2 Release by Membrane Stromal Cells Initiates Monosodium Urate Crystal-Induced Monocyte Recruitment in a Peritoneal Model of Gouty Inflammation

Monocyte recruitment is a characteristic feature of the inflammatory response to monosodium urate (MSU) crystals in gout, however the specific cell population(s) responsible for initiating this event is unclear. We therefore investigated the contribution of resident and stromal cell populations to the initiation of MSU crystal-induced inflammatory cytokine and chemokine production in a peritoneal murine model of gout. Depletion of resident macrophages decreased neutrophil infiltration but did not affect MSU crystal-induced monocyte recruitment in vivo despite a significant decrease in overall CCL2 production. Activation of isolated resident peritoneal cells and peritoneal membrane with MSU crystals in vitro indicated that resident peritoneal cells, more specifically resident macrophages, were primarily responsible for the production of the neutrophil chemokine CXCL1, whereas CCL2 was exclusively produced in membrane cultures. Primary culture of membrane mesothelial cells followed by MSU crystal stimulatio...

Effect of macelignan on inhibiting biomarkers of gouty inflammation in rat chondrocytes in vitro

Effect of macelignan on inhibiting biomarkers of gouty inflammation in rat chondrocytes in vitro

Microcrystals as DAMPs and their role in joint inflammation

Microcrystals associated with joint diseases, namely monosodium urate, calcium pyrophosphate and basic calcium phosphate, can be considered as 'danger signals' to the innate immune system and provoke inflammation through inflammasome-dependent as well as inflammasome-independent pathways. Direct crystal membrane interactions can also lead to cell activation. The result is the generation of IL-1β and other pro-inflammatory cytokines. The primacy of IL-1β in the case of gouty inflammation has been demonstrated by the efficacy of IL-1 inhibitors in clinical studies. These findings may be relevant to other diseases where crystal formation is found, such as OA and atherosclerosis.

Treatment of hyperuricemia, gout and other crystalline arthritidies

Gout is a very common joint disease which is due to chronic hyperuricemia and its related articular involvements. Yet it can be cured when appropriately managed. Comprehensive management of gout involves correct identification and addressing all causes of hyperuricemia, treating and preventing attacks of gouty inflammation (using colchicine NSAIDs, and/or steroids), and lowering serum urate (SUA) to an appropriate target level indefinitely. The ideal SUA target is, at a minimum, less than 6 mg/dL (60 mg/L or 360 μmol/L), or even less than 5 mg/dL in patients with tophi. The SUA target should remain at less than 6 mg/dL for long in all gout patients, especially until tophi have resolved. Patient education and adherence to therapy are key point to the optimal management of gout, aspects which are often neglected. Adherence can be monitored in part by continuing, regular assessment of the SUA level. More difficult cases of gout often need a combination of urate lowering therapy (ULT) for both refractory hyperuricemia and chronic tophaceous arthritis. Chronic tophaceous gouty arthropathy which do not respond adequately to optimized oral ULT might benefit from the use of pegloticase, when this is available in, for example, Italy and other European countries. By contrast, in calcium pyrophosphate (CPP) crystal deposition disease (CPPD), as evidenced by pseudo gout attacks or chronic polyarthritis, similar anti-inflammatory strategies have been recommended, but there have as yet been no controlled trials. Of note, there is no treatment for the underlying metabolic disorders able to control the CPPD. Management of crystal-induced arthropathies (CIA) depends not only on clinical expression, namely acute attacks or chronic arthropathy, but also on the underlying metabolic disorder. We will mainly focus on gout as an archetype of CIA.

Preventive effect of sesame oil on experimental acute gouty inflammation in rats

Preventive effect of sesame oil on experimental acute gouty inflammation in rats

New and emerging therapies for gout

After nearly 50 years, new drugs are now available or in development for gout. Febuxostat (approved 2009) selectively inhibits xanthine oxidase, preventing uric acid formation and lowering serum urate. Pegloticase (approved 2010) is a recombinant chimeric mammalian uricase that corrects the intrinsic human uricase deficiency. Pegloticase reduces serum urate, and may have particular efficacy against tophi. IL-1β is now understood to be a central actor in acute gouty inflammation. Three IL-1β antagonists – anakinra, rilonacept and canakinumab (all US FDA approved for other uses) – are being evaluated for gout treatment and/or prophylaxis. The renal urate resorbing transporters URAT1 and GLUT9 have been recently characterized as targets of uricosuric drugs; two pipeline drugs, RDEA594 and tranilast, inhibit these transporters and are promising urate-lowering therapies.

Gout

Once described as the disease of kings, gout has developed a much greater incidence and prevalence. The incidence of gout is on the rise predominantly in the elderly. There appears to be a greater risk of developing gout with hyperuricemia, hypertension, and renal disease. High fructose drinks, red meat, organ meats, fatty seafood, and beer or liquor also appear to increase the risk of developing gout. Gout can lead to inflammation and damage to cartilage, bone, bursa, tendons, heart, or kidneys. Patients with gout will have many years of asymptomatic hyperuricemia followed by episodes of acute gouty inflammation and asymptomatic periods. Some people with gout will progress to chronic gout with tophi deposits, pain, deformity, and bone and cartilage destruction.

Role of Melanocortin Receptors in the Regulation of Gouty Inflammation

Gouty arthritis is a form of acute joint inflammation provoked by joint deposition of urate crystals. Although this acute pathology resolves after a few days, the marked degree of inflammation in the joint and--possibly more important to the patient--the excruciating pain it causes require proper therapeutic management. Often deemed a "poor sibling" of chronic joint pathologies such as rheumatoid arthritis and psoriatic arthritis, the increasing incidence of gout makes it a more palatable disease for novel drug discovery programs. This fact, associated with novel insights into the molecular mechanisms activated by the urate crystal deposition, is at the basis of new therapeutics under clinical development for gout, a valid example being the effective targeting of the proinflammatory cytokine interleukin-1. Here we briefly review the current status of antigout drug development and propose another target; our focus is on melanocortin receptor agonists as novel therapeutics for gout and inflammatory arthritides, a prototype of which, the adrenocorticotropic hormone, is already used in clinical settings.

REVIEW: Management of gout: beyond allopurinol

AbstractThe basic concepts of the pathogenesis and management of gout have not altered for many years. Monosodium urate monohydrate crystals drive the disease and identification of these crystals is required for certain diagnosis. In contrast, our understanding of the mediators of gouty inflammation, the appropriate target serum urate concentration during treatment, the drugs available and the best ways to use those drugs have all advanced in recent years and will be the focus of this review.

Update on Biology: Uric Acid and the Activation of Immune and Inflammatory Cells

Gout is a common metabolic disorder characterized by elevated uric acid leading to the formation and accumulation of uric acid crystals in synovial fluids. An attack of gout is characterized by intense, self-limited bouts of acute arthritis with excruciating pain. The mechanisms regulating initiation and resolution of gouty inflammation are still unclear. A significant though incomplete body of information implicating the innate immune system as a central component of immune and inflammatory cell activation in gout has been accumulated over the past few years. In this review, advances in the understanding of the basic biology of crystal-mediated inflammation are summarized. The emerging role of the inflammasome and the cytokine interleukin-1 in the initiation of acute gout is highlighted. How these findings may open a door to a new approach for therapy with the development of interleukin-1 antagonists is discussed.

Update on gout: new therapeutic strategies and options

Gout, a disease recognized since antiquity, has increased in prevalence in recent years and the clinical profile of this disease has become increasingly complex, owing to large numbers of cases with iatrogenic factors, multiple comorbidities, advanced age, and hyperuricemia and arthritis refractory to treatment. In this Review, key advances in gout research made during the past decade are summarized. Revised strategies for safe and effective employment of dietary measures and pharmacologic treatments for active gouty arthritis, prevention of gout flares and urate lowering are also reviewed, with an emphasis on dosing of colchicine and allopurinol, and the evidence-based approach to systemic glucocorticosteroid treatment of acute gout. Also discussed are new and emerging treatments for gout and hyperuricemia, and the potential influence of dual energy CT imaging on treatment. In this context, the therapeutic role of febuxostat, and clinical development of pegylated uricase urate-lowering therapy and interleukin 1 antagonism for gouty inflammation are reviewed. Collectively, novel approaches will hopefully lead to improved management of hyperuricemia and gout, and also to improvements in patient-centered outcomes, even for those who have previously failed to respond to treatment.

The natural killer cell: a further innate mediator of gouty inflammation?

Natural killer (NK) cells are vital effector cells of innate immunity because of their rapid cytotoxic and cytokine-producing responses to cell stress or infection. A distinguishing feature of NK cells is the ability to balance these signals with those of normal homeostasis through the expression of an array of inhibitory and activating receptors. Two functional subsets of NK cells exist: the more mature CD56(dim) population is potently cytotoxic, whereas CD56(bright) NK cells have low cytotoxicity but produce much greater amounts of cytokines, and express homing molecules for secondary lymphoid organs and sites of inflammation. NK cells have been identified as important modulatory cells in shaping adaptive immune responses by interacting with dendritic cells (DCs) and T cells. NK cells also interact with cells of the innate immune system such as monocytes and macrophages. This review outlines the biology of NK cells and the potential role of NK cells in modulating gouty inflammation.

Sesquiterpene dialdehydes inhibit MSU crystal-induced superoxide production by infiltrating neutrophils in an in vivo model of gouty inflammation

A hallmark feature of monosodium urate (MSU) crystal-induced inflammation in gouty arthritis is the infiltration of activated neutrophils into the joint. Therefore inhibition of neutrophil superoxide production is a rational target for treating inflammation in gout. The natural product polygodial and related sesquiterpene dialdehyde analogs were tested in vitro and in vivo for their ability to inhibit neutrophil infiltration and superoxide production in response to MSU crystal stimulation. Polygodial and other sesquiterpene dialdehydes exhibited dose-dependent inhibition of MSU-induced superoxide production in the micromolar and submicromolar ranges. Inhibition of superoxide production was dependent on the presence of the dialdehyde functional groups and was sensitive to blockade with the thiol-containing amino acid cysteine. Polygodial, 6-hydroxypaxidal and sesquiterpene 2 inhibited both neutrophil infiltration and neutrophil superoxide production in an MSU crystal-induced mouse model of gouty inflammation. Together, these data highlight the potential of sesquiterpene dialdehydes for development as anti-inflammatory agents for the treatment of neutrophil-driven inflammatory diseases including gout.

A role of IgM antibodies in monosodium urate crystal formation and associated adjuvanticity (135.71)

Abstract Uric acid is a product of purine metabolism that is secreted from injured or dying cells and can act as an endogenous adjuvant. However, uric acid must crystallize to monosodium urate (MSU) before it can activate dendritic cells and cause gouty inflammation. At normal serum uric acid levels, crystallization of uric acid is not observed in vitro. The crucial question therefore is how the crystals form and cause inflammation. It has been reported that serum from rabbits immunized with MSU, increased uric acid precipitation rates. When C57BL6 or Balb/c mice were immunized with MSU, they produced serum factors which bind to MSU crystals, a phenomenon absent in mu chain deficient IgH (or muMT) mice. These observations show that antibodies may be involved in MSU crystallization. Antibodies produced via B cell hybridomas, were observed to precipitate uric acid in vitro, with the variable region acting as the binding domain. Most importantly, the presence of antibody was instrumental in significantly increasing the basal level of inflammation and mediating the adjuvant effect of uric acid in antigen dependent T cell cytotoxicity in B cell deficient mice. Therefore, we have identified a factor in determining uric acid precipitation and possibly its ability to function as an endogenous adjuvant. This finding suggests a new mechanism of the pathogenesis of gouty arthritis and uric acid induced immune activation.

Gout. Novel therapies for treatment of gout and hyperuricemia.

In the past few decades, gout has increased not only in prevalence, but also in clinical complexity, the latter accentuated in part by a dearth of novel advances in treatments for hyperuricemia and gouty arthritis. Fortunately, recent research reviewed here, much of it founded on elegant translational studies of the past decade, highlights how gout can be better managed with cost-effective, well-established therapies. In addition, the advent of both new urate-lowering and anti-inflammatory drugs, also reviewed here, promises for improved management of refractory gout, including in subjects with co-morbidities such as chronic kidney disease. Effectively delivering improved management of hyperuricemia and gout will require a frame shift in practice patterns, including increased recognition of the implications of refractory disease and frequent noncompliance of patients with gout, and understanding the evidence basis for therapeutic targets in serum urate-lowering and gouty inflammation.

SIGNIFICANCE OF DIET AND DIETARY SUPPLEMENTS IN GOUT

The paper discusses a role of a diet and therapy with the herbal complex Urisan in patients with gout. It is noted that the agent based on herbal components may be used in addition to drug therapy and diet in seasonal hyperuricuria, hyperuricemia observed after heavy strenuous and athletic activity, meat overeating, and alcohol abuse. Urisan may be recommended in subsiding gouty inflammation as a bridge to the use of allopurinol.

Orthidines A–E, tubastrine, 3,4-dimethoxyphenethyl-β-guanidine, and 1,14-sperminedihomovanillamide: potential anti-inflammatory alkaloids isolated from the New Zealand ascidian Aplidium orthium that act as inhibitors of neutrophil respiratory burst

In addition to the known dihydroxystyrylguanidine alkaloid tubastrine ( 1), five new dimers, orthidines A–E ( 2– 6) and the biosynthetically unrelated 1,14-sperminedihomovanillamide (orthidine F, 7) were isolated from the New Zealand ascidian Aplidium orthium. The structures of the new compounds, elucidated by interpretation of spectroscopic data, encompass benzodioxane neolignan-type scaffolds ( 2– 5) and a 1,2,3,4-tetrasubstituted cyclobutane ( 6), the latter likely having arisen via [ π2 s+ π2 s] dimerization of tubastrine. The subunit head-to-tail orientation of dimer 6 was established unambiguously by interpretation of data from a 2 J, 3 J-HMBC NMR experiment. The structure of 7 was also confirmed by facile synthesis. Compounds 1– 4, 6, and 7 inhibited the in vitro production of superoxide by PMA-stimulated human neutrophils in a dose-dependent manner with IC 50s of 10–36 μM and this was associated with inhibition of superoxide production by neutrophils in vivo in a murine model of gouty inflammation.

Colchicine suppresses neutrophil superoxide production in a murine model of gouty arthritis: a rationale for use of low‐dose colchicine

When used to treat gouty arthritis, colchicine is believed to work by inhibiting microtubule-dependent cell infiltration. However, in vitro, colchicine also reduces monosodium urate (MSU)-induced superoxide production by neutrophils. Our study aimed to compare the effects of colchicine on neutrophil superoxide production and infiltration in an in vivo model of acute gouty inflammation. In vitro: Human and murine peritoneal neutrophils were incubated with MSU with and without colchicine, and superoxide production was measured. In vivo: Mice were treated with colchicine followed by an intraperitoneal injection of MSU to induce acute inflammation. After 4h, the peritoneal cells were recovered to measure superoxide production and neutrophil infiltration. Sera were tested for liver and renal toxicity. Colchicine dose-dependently inhibited MSU-induced superoxide production by both human and murine neutrophils in vitro. Oral colchicine inhibited MSU-induced superoxide production by neutrophils in vivo at doses 100 times lower than those required to inhibit neutrophil infiltration and without acute liver or renal toxicity. Neutrophils treated with colchicine in vivo still produced superoxide in response to another stimulus, 4-beta-phorbol-12-myristate-13-acetate. These results show a beneficial effect of colchicine for the treatment of MSU-induced superoxide production in vivo at sub-toxic doses without compromising superoxide production by other physiological processes. This is the first in vivo data to provide a biological rationale that supports the implementation of low dose, non-toxic, colchicine therapy for the treatment of gouty arthritis.

Gout in the spotlight

Understanding how uric acid crystals provoke inflammation is crucial to improving our management of acute gout. It is well known that urate crystals stimulate monocytes and macrophages to elaborate inflammatory cytokines, but the tissue response of the synovium is less well understood. Microarray analysis of mRNA expression by these lining cells may help to delineate the genes that are modulated. Employing a murine air-pouch model, a number of genes expressed by innate immune cells were found to be rapidly upregulated by monosodium urate crystals. These findings provide new research avenues to investigate the physiopathology of gouty inflammation, and may eventually lead to new therapeutic targets in acute gout.

Therapeutic advances in gout

The purpose of this review is to highlight the recent developments in the management of gout. Guidelines for the diagnosis and management of gout from EULAR, quality of care indicators, and outcome measures for clinical trials have been published. The standards of gout diagnosis and management are very low. Allopurinol remains the mainstay for serum uric acid lowering therapy. In an important percentage of patients receiving allopurinol, serum uric acid levels are insufficient to promote crystal dissolution. Febuxostat, a new serum uric acid lowering drug, has shown good results. Information on uricase continues to appear. For treatment of gouty inflammation, etoricoxib (a new cyclooxygenase 2 inhibitor) has been shown to be as effective as indomethacin. Finally, the association of gout with the metabolic syndrome and its comorbidities, and the newly described association of gout with myocardial infarction, bring lifestyle and dietary modifications to the front in the management of gout. Proper gout management requires changes to the physician's attitude towards the disease; essentially: (1) an unequivocal diagnosis based in urate crystal identification, (2) a clearly settled aim of the treatment: crystal elimination from the joints and elsewhere, and (3) proper use of the available therapeutic alternatives. Promoting a proper lifestyle appears to be especially important.