The development from hyperuricemia to gout: key mechanisms and natural products for treatment

Abstract

Gout is a common of inflammatory arthritis and is caused by the deposition of monosodium urate (MSU) crystals as a result of hyperuricemia (HUA). Although HUA is considered to be the main risk factor for gout, only approximately 10% of the individuals with HUA will eventually experience a gout attack. In this review, we first briefly introduce the development of gout and then summarize several possible reasons for its development. Genetic factors play a more prominent role in gout than in other diseases; functional mutations related to urate control and innate immunity components have been found to be associated with gout. Here, we list some of the most prominent genes involved in the pathogenesis of gout. In joints with MSU deposition, mature macrophages may uptake MSU crystals without causing inflammation, and this helps to maintain joints in an asymptomatic state. As an auxiliary inflammation pathway, the ATP-P2X7R-NLRP3 axis may contribute to the amplification of MSU-induced inflammation to affect the development of gout. Finally, this review summarizes the research progress on natural products that can be used in the treatment of HUA and gout.

Keywords

ATP-P2X7R-NLRP3 axis / Gout / Hyperuricemia / MSU-related inflammation / Natural products

References

[[1]] Kuo CF, Grainge MJ, Zhang W, et al. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol 2015; 11(11):649-662.

[[2]] Yu KH, Chen DY, Chen JH, et al. Management of gout and hyperuricemia: multidisciplinary consensus in Taiwan. Int J Rheum Dis 2018; 21(4):772-787.

[[3]] Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum 2011; 63 (10):3136-3141.

[[4]] Mandell B. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med 2008; 75(Suppl 5):S5-8.

[[5]] Dalbeth N, Merriman T. Crystal ball gazing: new therapeutic targets for hyperuricaemia and gout. Rheumatology 2009; 48 (3):222-226.

[[6]] Dalbeth N, Choi H, Joosten L, et al. Gout. Nat Rev Dis Primers 2019; 5(1):69.

[[7]] Dalbeth N, Merriman T, Stamp L. Gout. Lancet 2016; 388 (10055):2039-2052.

[[8]] Nakayama A, Matsuo H, Nakaoka H, et al. Common dysfunctional variants of ABCG 2 have stronger impact on hyperuricemia progression than typical environmental risk factors. Sci Rep 2014; 4:5227.

[[9]] Dalbeth N, Phipps-Green A, Frampton C, et al. Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis. Ann Rheum Dis 2018; 77(7):1048-1052.

[[10]] Perez-Ruiz F, Calabozo M, Erauskin GG, et al. Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum 2002; 47(6):610-613.

[[11]] Yang B, Mo Z, Wu C, et al. A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population. BMC Med Genomics 2014; 7:10.

[[12]] Merriman T. Population heterogeneity in the genetic control of serum urate. Semin Nephrol 2011; 31(5):420-425.

[[13]] Köttgen A, Albrecht E, Teumer A, et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 2013; 45(2):145-154.

[[14]] Phipps-Green A, Merriman M, Topless R, et al. Twenty-eight loci that influence serum urate levels: analysis of association with gout. Ann Rheum Dis 2016; 75(1):124-130.

[[15]] Wrigley R, Phipps-Green A, Topless R, et al. Pleiotropic effect of the ABCG 2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout. Arthritis Res Ther 2020; 22(1):45.

[[16]] Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7:43614.

[[17]] Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 2008; 372(9654):1953-1961.

[[18]] Qing YF, Zhang QB, Zhou JG. Innate immunity functional gene polymorphisms and gout susceptibility. Gene 2013; 524 (2):412-414.

[[19]] Chang WC, Jan Wu YJ, Chung WH, et al. Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis. Rheumatology 2017;(3):457-466.

[[20]] Chang W, Jan WY, Chung W, et al. Genetic variants of PPARgamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis. Rheumatology (Oxford, England) 2017; 56 (3):457-466.

[[21]] Liu S, Zhou Z, Wang C, et al. Associations between interleukin and interleukin receptor gene polymorphisms and risk of gout. Sci Rep 2015; 5:13887.

[[22]] McKinney C, Stamp L, Dalbeth N, et al. Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout. Arthritis Res Ther 2015; 17(1):288.

[[23]] Kawamura Y, Nakaoka H, Nakayama A, et al. Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout. Ann Rheum Dis 2019; 78 (10):1430-1437.

[[24]] Mandel NS, Mandel GS. Monosodium urate monohydrate, the gout culprit. J Am Chem Soc 1976; 98(8):2319-2323.

[[25]] Molloy RGE, Sun WH, Chen JL, et al. Structure and cleavage of monosodium urate monohydrate crystals. Chem Commun (Cambridge, England) 2019; 55(15):2178-2181.

[[26]] Perrin CM, Dobish MA, Keuren EV, et al. Monosodium urate monohydrate crystallization. CrystEngComm 2011; 13 (4):1111-1117.

[[27]] Pascual E, Addadi L, Andrés M, et al. Mechanisms of crystal formation in gout-a structural approach. Nat Rev Rheumatol 2015; 11(12):725-730.

[[28]] Chhana A, Lee G, Dalbeth N. Factors influencing the crystallization of monosodium urate: a systematic literature review. BMC Musculoskelet Disord 2015; 16(1):296.

[[29]] Schlesinger N, Norquist JM, Watson DJ. Serum urate during acute gout. J Rheumatol 2009; 36(6):1287-1289.

[[30]] Dalbeth N, House ME, Aati O, et al. Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study. Ann Rheum Dis 2015; 74(5):908-911.

[[31]] Shi Y, Mucsi AD, Ng G. Monosodium urate crystals in inflammation and immunity. Immunol Rev 2010; 233(1): 203-217.

[[32]] Nazzal Martillo MA, Crittenden DB. The crystallization of monosodium urate. Curr Rheumatol Rep 2014; 16(1):400.

[[33]] Martínez Sanchis A, Pascual E. Intracellular and extracellular CPPD crystals are a regular feature in synovial fluid from uninflamed joints of patients with CPPD related arthropathy. Ann Rheum Dis 2005; 64(12):1769-1772.

[[34]] Yagnik D, Hillyer P, Marshall D, et al. Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages: implications for the control of joint inflammation in gout. Arthritis Rheum 2000; 43(8):1779-1789.

[[35]] Landis R, Yagnik D, Florey O, et al. Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages. Arthritis Rheum 2002; 46(11):3026-3033.

[[36]] Yagnik D. Macrophage derived platelet activating factor implicated in the resolution phase of gouty inflammation. Int J Inflam 2014; 2014(9):526496.

[[37]] Puig J, de Miguel E, Castillo M, et al. Asymptomatic hyperuricemia: impact of ultrasonography. Nucleosides Nucleotides Nucleic Acids 2008; 27(6):592-595.

[[38]] Estevez-Garcia I, Gallegos-Nava S, Vera-Pérez E, et al. Levels of cytokines and microRNAs in individuals with asymptomatic hyperuricemia and ultrasonographic findings of gout: a bench-tobedside approach. Arthritis Care Res 2018; 70(12):1814-1821.

[[39]] Tao JH, Zhang Y, Li XP. P2X7R: a potential key regulator of acute gouty arthritis. Semin Arthritis Rheum 2013; 43(3):376-380.

[[40]] Gong QY, Chen Y. Correlation between P2X7 receptor gene polymorphisms and gout. Rheumatol Int 2015; 35(8):1307-1310.

[[41]] Lee S, Lee S, Oh D, et al. Genetic Association for P2X7R rs3751142 and CARD 8 rs2043211 polymorphisms for susceptibility of gout in Korean men: multi-center study. J Korean Med Sci 2016; 31(10):1566-1570.

[[42]] Gicquel T, Le Daré B, Boichot E, et al. Purinergic receptors: new targets for the treatment of gout and fibrosis. Fundam Clin Pharmacol 2017; 31(2):136-146.

[[43]] Franceschini A, Capece M, Chiozzi P, et al. The P2X 7 receptor directly interacts with the NLRP3 inflammasome scaffold protein. FASEB J 2015; 29(6):2450-2461.

[[44]] Karmakar M, Katsnelson MA, Dubyak GR, et al. Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1b secretion in response to ATP. Nat Commun 2016; 7(4):10555.

[[45]] Englezou PC, Rothwell SW, Ainscough JS, et al. P2X7R activation drives distinct IL-1 responses in dendritic cells compared to macrophages. Cytokine 2015; 74(2):293-304.

[[46]] Gustin A, Kirchmeyer M, Koncina E, et al. NLRP 3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. Plos One 2015; 10(6):e0130624.

[[47]] Aude B, Vincent L, Catherine R, et al. IL-1b production is dependent on the activation of purinergic receptors and NLRP 3 pathway in human macrophages. Faseb J 2015; 29 (10):4162-4173.

[[48]] Pascart T, Grandjean A, Capon B, et al. Monosodium urate burden assessed with dual-energy computed tomography predicts the risk of flares in gout: a 12-month observational study: MSU burden and risk of gout flare. Arthritis Res Ther 2018; 20(1):210.

[[49]] Ma Q, Honarpisheh M, Li C, et al. Soluble uric acid is an intrinsic negative regulator of monocyte activation in monosodium urate crystal-induced tissue inflammation. J Immunol 2020; 205(3):789-800.

[[50]] Serrano J, Figueiredo J, Almeida P, et al. In vivo from xanthine oxidase inhibition to hypouricemic effect: an integrated overview of and studies with focus on natural molecules and analogues. Evid Based Complement Alternat Med 2020; 2020(4):9531725.

[[51]] Hu Q, Zhang X, Wang X, et al. Quercetin regulates organic ion transporter and uromodulin expression and improves renal function in hyperuricemic mice. Eur J Nutr 2012; 51(5):593-606.

[[52]] Zhang C, Wang R, Zhang G, et al. Mechanistic insights into the inhibition of quercetin on xanthine oxidase. Int J Biol Macromol 2018; 112(7):405-412.

[[53]] Ruiz-Miyazawa KW, Staurengo-Ferrari L, Mizokami SS, et al. Quercetin inhibits gout arthritis in mice: induction of an opioiddependent regulation of inflammasome. Inflammopharmacology 2017; 25(4):550-570.

[[54]] Wang M, Zhao J, Zhang N, et al. Astilbin improves potassium oxonate-induced hyperuricemia and kidney injury through regulating oxidative stress and inflammation response in mice. Biomed Pharmacother 2016; 83(8):975-988.

[[55]] Shi Y, Wang C, Liu L, et al. Antihyperuricemic and nephroprotective effects of resveratrol and its analogues in hyperuricemic mice. Mol Nutr Food Res 2012; 56(9):1433-1444.

[[56]] Li H, Ou G, He Y, et al. Resveratrol attenuates the MSU crystalinduced inflammatory response through the inhibition of TAK1 activity. Int Immunopharmacol 2019; 67(4):62-68.

[[57]] Wu X, Ruan J, Zhang J, et al. Pallidifloside D, a saponin glycoside constituent from Smilax riparia, resist to hyperuricemia based on URAT1 and GLUT 9 in hyperuricemic mice. J Ethnopharmacol 2014; 157(12):201-205.

[[58]] Hou P, Mi C, He Y, et al. Pallidifloside D from Smilax riparia enhanced allopurinol effects in hyperuricemia mice. Fitoterapia 2015; 105(9):43-48.

[[59]] Zhou Q, Yu D, Zhang N, et al. Anti-inflammatory effect of total saponin fraction from Dioscorea nipponica Makino on gouty arthritis and its influence on NALP3 inflammasome. Chin J Integr Med 2019; 25(9):663-670.

[[60]] Zhang Y, Jin L, Liu J, et al. Effect and mechanism of dioscin from Dioscorea spongiosa on uric acid excretion in animal model of hyperuricemia. J Ethnopharmacol 2018; 214(3):29-36.

[[61]] Anoopkumar K, Krishnan V. Asymptomatic hyperuricemia: is it time to intervene? Clin Rheumatol 2017; 36(12):2637-2644.