Gout is a common crystal-induced arthritis, in which monosodium urate (MSU) crystals precipitate within joints and soft tissues and elicit an inflammatory response. The causes of elevated serum urate and the inflammatory pathways activated by MSU crystals have been well studied, but less is known about the processes leading to crystal formation and growth. Uric acid, the final product of purine metabolism, is a weak acid that circulates as the deprotonated urate anion under physiologic conditions, and combines with sodium ions to form MSU. MSU crystals are known to have a triclinic structure, in which stacked sheets of purine rings form the needle-shaped crystals that are observed microscopically. Exposed, charged crystal surfaces are thought to allow for interaction with phospholipid membranes and serum factors, playing a role in the crystal-mediated inflammatory response. While hyperuricemia is a clear risk factor for gout, local factors have been hypothesized to play a role in crystal formation, such as temperature, pH, mechanical stress, cartilage components, and other synovial and serum factors. Interestingly, several studies suggest that MSU crystals may drive the generation of crystal-specific antibodies that facilitate future MSU crystallization. Here, we review MSU crystal biology, including a discussion of crystal structure, effector function, and factors thought to play a role in crystal formation. We also briefly compare MSU biology to that of uric acid stones causing nephrolithasis, and consider the potential treatment implications of MSU crystal biology.
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The authors thank David Goldfarb and Michael Pillinger for helpful input with the text, and Michael Ward for reviewing the accuracy of the figures.
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Conflict of Interest
This work was supported in part by grants from the Arthritis Foundation and New York Academy of Medicine (to Daria B. Crittenden), and by grant UL1 TR000038 from the National Center for Advancing Translational Sciences, National Institutes of Health.
Miguel A. Martillo, Lama Nazzal, and Daria B. Crittenden declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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Busso N, So A. Microcrystals as DAMPs and their role in joint inflammation. Rheumatology (Oxford). 2012;51(7):1154–60.CrossRefGoogle Scholar
Martinon F et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–41.PubMedCrossRefGoogle Scholar
Pettipher ER, Higgs GA, Henderson B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci U S A. 1986;83(22):8749–53.PubMedCentralPubMedCrossRefGoogle Scholar
Weinberger A, Schumacher HR, Agudelo CA. Urate crystals in asymptomatic metatarsophalangeal joints. Ann Intern Med. 1979;91(1):56–7.PubMedCrossRefGoogle Scholar
Lin KC, Lin HY, Chou P. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J Rheumatol. 2000;27(6):1501–5.PubMedGoogle Scholar
Hall AP et al. Epidemiology of gout and hyperuricemia. A long-term population study. Am J Med. 1967;42(1):27–37.PubMedCrossRefGoogle Scholar
Frincu MC, Fogarty CE, Swift JA. Epitaxial relationships between uric acid crystals and mineral surfaces: a factor in urinary stone formation. Langmuir. 2004;20(16):6524–9.PubMedCrossRefGoogle Scholar
•• Perrin CM et al. Monosodium urate monohydrate crystallization. CrystEngComm. 2011;13(4):1111–7. Modern-day work in which in situ atomic force microscopy and dynamic light scattering were used to elucidate the growth of monosodium urate crystals on a molecular level.CrossRefGoogle Scholar
Ortiz-Bravo E, Sieck MS, Schumacher Jr HR. Changes in the proteins coating monosodium urate crystals during active and subsiding inflammation. Immunogold studies of synovial fluid from patients with gout and of fluid obtained using the rat subcutaneous air pouch model. Arthritis Rheum. 1993;36(9):1274–85.PubMedCrossRefGoogle Scholar
Cherian PV, Schumacher Jr HR. Immunochemical and ultrastructural characterization of serum proteins associated with monosodium urate crystals (MSU) in synovial fluid cells from patients with gout. Ultrastruct Pathol. 1986;10(3):209–19.PubMedCrossRefGoogle Scholar
Kozin F, McCarty DJ. Molecular orientation of immunoglobulin G adsorbed to microcrystalline monosodium urate monohydrate. J Lab Clin Med. 1980;95(1):49–58.PubMedGoogle Scholar
Terkeltaub R et al. Plasma protein binding by monosodium urate crystals. Analysis by two-dimensional gel electrophoresis. Arthritis Rheum. 1983;26(6):775–83.PubMedCrossRefGoogle Scholar
Mullin JW. Nucleation In Crystallization. Oxford: Butterworth-Heinemann; 1993. p. 172–201.Google Scholar
Fiddis RW, Vlachos N, Calvert PD. Studies of urate crystallisation in relation to gout. Ann Rheum Dis. 1983;42 Suppl 1:12–5.PubMedCrossRefGoogle Scholar
Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004;51(3):321–5.PubMedCrossRefGoogle Scholar
Allen DJ, Milosovich G, Mattocks AM. Inhibition of monosodium urate needle crystal growth. Arthritis Rheum. 1965;8(6):1123–33.PubMedCrossRefGoogle Scholar
Loeb JN. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum. 1972;15(2):189–92.PubMedCrossRefGoogle Scholar
McGill NW, Dieppe PA. Evidence for a promoter of urate crystal formation in gouty synovial fluid. Ann Rheum Dis. 1991;50(8):558–61.PubMedCrossRefGoogle Scholar
Tak HK, Cooper SM, Wilcox WR. Studies on the nucleation of monosodium urate at 37 degrees c. Arthritis Rheum. 1980;23(5):574–80.PubMedCrossRefGoogle Scholar
Burt HM, Dutt YC. Growth of monosodium urate monohydrate crystals: effect of cartilage and synovial fluid components on in vitro growth rates. Ann Rheum Dis. 1986;45(10):858–64.PubMedCrossRefGoogle Scholar
• Pascual E, Martinez A, Ordonez S. Gout: the mechanism of urate crystal nucleation and growth. A hypothesis based in facts. Joint Bone Spine. 2013;80(1):1–4. A recent review that summarizes information gleaned from current imaging of gouty joints, and a hypothesis regarding what this may teach us about monosodium urate crystallization.PubMedCrossRefGoogle Scholar
Katz WA. Role of proteoglycans in the development of gouty arthritis. In: Weiner IM, Kelley WN, editors. Handbook of Experimental Pharmacology. New York: Springer; 1978. p. 347–64.Google Scholar
Perl-Treves D, Addadi L. A structural approach to pathological crystallizations. Gout: the possible role of albumin in sodium urate crystallization. Proc R Soc Lond B Biol Sci. 1988;235(1279):145–59.PubMedCrossRefGoogle Scholar
Kaneko K, Maru M. Determination of urate crystal formation using flow cytometry and microarea X-ray diffractometry. Anal Biochem. 2000;281(1):9–14.PubMedCrossRefGoogle Scholar
Terkeltaub R et al. Low density lipoprotein inhibits the physical interaction of phlogistic crystals and inflammatory cells. Arthritis Rheum. 1986;29(3):363–70.PubMedCrossRefGoogle Scholar
Scanu A et al. High-density lipoproteins downregulate CCL2 production in human fibroblast-like synoviocytes stimulated by urate crystals. Arthritis Res Ther. 2010;12(1):11.CrossRefGoogle Scholar
McGill NW, Hayes A, Dieppe PA. Morphological evidence for biological control of urate crystal formation in vivo and in vitro. Scand J Rheumatol. 1992;21(5):215–9.PubMedCrossRefGoogle Scholar
Thiele RG. Role of ultrasound and other advanced imaging in the diagnosis and management of gout. Curr Rheumatol Rep. 2011;13(2):146–53.PubMedCrossRefGoogle Scholar
Howard RG et al. Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: Concordance between readers. Arthritis Care & Research. 2011;63(10):1456–62.CrossRefGoogle Scholar
Hesse A et al. Uric acid dihydrate as urinary calculus component. Invest Urol. 1975;12(5):405–9.PubMedGoogle Scholar
Sakhaee K et al. Assessment of the pathogenetic role of physical exercise in renal stone formation. J Clin Endocrinol Metab. 1987;65(5):974–9.PubMedCrossRefGoogle Scholar
Grover PK, Marshall VR, Ryall RL. Dissolved urate salts out calcium oxalate in undiluted human urine in vitro: implications for calcium oxalate stone genesis. Chem Biol. 2003;10(3):271–8.PubMedCrossRefGoogle Scholar
Ettinger B et al. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med. 1986;315(22):1386–9.PubMedCrossRefGoogle Scholar
Pak CY et al. Mechanism for calcium urolithiasis among patients with hyperuricosuria: supersaturation of urine with respect to monosodium urate. J Clin Invest. 1977;59(3):426–31.PubMedCentralPubMedCrossRefGoogle Scholar
Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis. 2007;66(8):1056–8.PubMedCrossRefGoogle Scholar
Thiele RG, Schlesinger N. Ultrasonography shows disappearance of monosodium urate crystal deposition on hyaline cartilage after sustained normouricemia is achieved. Rheumatol Int. 2010;30(4):495–503.PubMedCrossRefGoogle Scholar