Current Rheumatology Reports

, Volume 12, Issue 2, pp 142–148 | Cite as

The Role of Uric Acid and Other Crystals in Osteoarthritis

  • Johannes NowatzkyEmail author
  • Rennie Howard
  • Michael H. Pillinger
  • Svetlana Krasnokutsky


Clinicians have long assumed that an association exists between crystal arthropathies and the presence of osteoarthritis (OA). However, studies establishing an independent association between calcium pyrophosphate or uric acid crystal disease and OA are sparse. Even less is known about a possible pathogenic relationship. Whereas some studies suggest that the relationships between crystals and OA may not be incidental and that crystal deposition may contribute to the onset and/or acceleration of OA joint damage, other authors have challenged this assertion. In this review, we provide an overview of past and current research elucidating the role of crystal deposition, including monosodium urate, calcium pyrophosphate, and other crystals, in OA. Given the clinical frequency of gout and that agents exist to modulate serum UA levels, special attention is given to the role of monosodium urate crystals.


Crystal arthropathy Osteoarthritis Uric acid Calcium pyrophosphate 



No potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Doherty M, Dieppe P: Clinical aspects of calcium pyrophosphate dehydrate crystal deposition. Rheum Dis Clin North Am 1988, 14:395–414.PubMedGoogle Scholar
  2. 2.
    •• Roddy E, Zhang W, Doherty M: Gout and nodal osteoarthritis: a case-control study. Rheumatology (Oxford) 2008, 47:732–733. This was one of the rare studies that investigated a possible relationship between gout and OA as its primary objective.CrossRefGoogle Scholar
  3. 3.
    Anderson JJ, Felson DT: Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work. Am J Epidemiol 1988, 128:179–189.PubMedGoogle Scholar
  4. 4.
    Felson DT, Zhang Y, Anthony JM, et al.: Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study. Ann Intern Med 1992, 116:535–539.PubMedGoogle Scholar
  5. 5.
    Schouten JS, van den Ouweland FA, Valkenburg HA: A 12 year follow up study in the general population on prognostic factors of cartilage loss in osteoarthritis of the knee. Ann Rheum Dis 1992, 51:932–937.CrossRefPubMedGoogle Scholar
  6. 6.
    Sun Y, Brenner H, Sauerland S, et al.: Serum uric acid and patterns of radiographic osteoarthritis—the Ulm Osteoarthritis Study. Scand J Rheumatol 2000, 29:380–386.CrossRefPubMedGoogle Scholar
  7. 7.
    Acheson RM, Collart AB: New Haven survey of joint diseases. XVII. Relationship between some systemic characteristics and osteoarthrosis in a general population. Ann Rheum Dis 1975, 34:379–387.CrossRefPubMedGoogle Scholar
  8. 8.
    Lally EV, Ho G Jr, Kaplan SR: The clinical spectrum of gouty arthritis in women. Arch Intern Med 1986, 146:2221–2225.CrossRefPubMedGoogle Scholar
  9. 9.
    Simkin PA, Campbell PM, Larson EB: Gout in Heberden’s nodes. Arthritis Rheum 1983, 26:94–97.CrossRefPubMedGoogle Scholar
  10. 10.
    Lally EV, Zimmermann B, Ho G Jr, Kaplan SR: Urate-mediated inflammation in nodal osteoarthritis: clinical and roentgenographic correlations. Arthritis Rheum 1989, 32:86–90.CrossRefPubMedGoogle Scholar
  11. 11.
    Roddy E, Zhang W, Doherty M: Are joints affected by gout also affected by osteoarthritis? Ann Rheum Dis 2007, 66:1374–1377.CrossRefPubMedGoogle Scholar
  12. 12.
    Laurent TC: Solubility of sodium urate in the presence of chondroitin-4-sulphate. Nature 1964, 202:1334.CrossRefPubMedGoogle Scholar
  13. 13.
    Katz WA, Schubert M: The interaction of monosodium urate with connective tissue components. J Clin Invest 1970, 49:1783–1789.CrossRefPubMedGoogle Scholar
  14. 14.
    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, 45:858–864.CrossRefPubMedGoogle Scholar
  15. 15.
    • Muehleman C, Li J, Aigner T, et al.: Association between crystals and cartilage degeneration in the ankle. J Rheumatol 2008, 35:1108–1117. This was a large, well-designed study investigating the prevalence, histologic, and biomechanical effects of MSU and CPP crystals on cartilage in the human ankle. A predominantly biomechanical effect was found to be induced by both MSU and CCP crystals.PubMedGoogle Scholar
  16. 16.
    Malawista SE, Duff GW, Atkins E, et al.: Crystal-induced endogenous pyrogen production. A further look at gouty inflammation. Arthritis Rheum 1985, 28:1039–1046.CrossRefPubMedGoogle Scholar
  17. 17.
    Di Giovine FS, Malawista SE, Nuki G, Duff GW: Interleukin 1 (IL 1) as a mediator of crystal arthritis. Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL 1. J Immunol 1987, 138:3213–3218.PubMedGoogle Scholar
  18. 18.
    Gowen M, Wood DD, Ihrie EJ, et al.: An interleukin 1 like factor stimulates bone resorption in vitro. Nature 1983, 306:378–380.CrossRefPubMedGoogle Scholar
  19. 19.
    Heath JK, Saklatvala J, Meikle MC, et al.: Pig interleukin 1 (catabolin) is a potent stimulator of bone resorption in vitro. Calcif Tissue Int 1985, 37:95–97.CrossRefPubMedGoogle Scholar
  20. 20.
    Liu-Bryan R, Scott P, Sydlaske A, et al.: Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 2005, 52:2936–2946.CrossRefPubMedGoogle Scholar
  21. 21.
    Martinon F, Pétrilli V, Mayor A, et al.: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440:237–241.CrossRefPubMedGoogle Scholar
  22. 22.
    Alwan WH, Dieppe PA, Elson CJ, Bradfield JW: Hydroxyapatite and urate crystal induced cytokine release by macrophages. Ann Rheum Dis 1989, 48:476–482.CrossRefPubMedGoogle Scholar
  23. 23.
    Smith MD, Triantafillou S, Parker A, et al.: Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 1997, 24:365–371.PubMedGoogle Scholar
  24. 24.
    Warnock MG, Sharif M, Elson CJ: IL-1-beta at physiological concentration stimulates degradation of human articular cartilage. Bone Miner 1994; 25(Suppl):S36.Google Scholar
  25. 25.
    Liu R, Lioté F, Rose DM, et al.: Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate crystal-induced nitric oxide production and matrix metalloproteinase 3 expression in chondrocytes. Arthritis Rheum 2004, 50:247–258.CrossRefPubMedGoogle Scholar
  26. 26.
    Abramson SB: Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Res Ther 2008, 10(Suppl 2):S2.CrossRefPubMedGoogle Scholar
  27. 27.
    • Liu L, Inoue H, Nakayama H, et al.: The endogenous danger signal uric acid augments contact hypersensitivity responses in mice. Pathobiology 2007, 74:177–185. This article introduced a new and important concept.CrossRefPubMedGoogle Scholar
  28. 28.
    Benko S, Philpott DJ, Girardin SE: The microbial and danger signals that activate NOD-like receptors. Cytokine 2008, 43:368–373.CrossRefPubMedGoogle Scholar
  29. 29.
    Gasse P, Riteau N, Charron S, et al.: Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med 2009, 179:903–913.CrossRefPubMedGoogle Scholar
  30. 30.
    Behrens MD, Wagner WM, Krco CJ, et al.: The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity. Blood 2008, 111:1472–1479.CrossRefPubMedGoogle Scholar
  31. 31.
    Stabler TV, Heinrichs A, McDaniel G, et al.: Synovial fluid uric acid as a marker of joint tissue degradation in osteoarthritis [abstract]. Osteoarthr Cartil 2009, 17:S68–S69.CrossRefGoogle Scholar
  32. 32.
    Zitnan D, Sitaj S: Chondrocalcinosis polyarticularis (familiaris): roentgenological and clinical analysis. Cesk Rentgenol 1960, 14:27–34.PubMedGoogle Scholar
  33. 33.
    Derfus BA, Kurian JB, Butler JJ, et al.: The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol 2002, 29:570–574.PubMedGoogle Scholar
  34. 34.
    Pattrick M, Hamilton E, Wilson R, et al.: Association of radiographic changes of osteoarthritis, symptoms, and synovial fluid particles in 300 knees. Ann Rheum Dis 1993, 52:97–103.CrossRefPubMedGoogle Scholar
  35. 35.
    Neame RL, Carr AJ, Muir K, Doherty M: UK community prevalence of knee chondrocalcinosis: evidence that correlation with osteoarthritis is through a shared association with osteophyte. Ann Rheum Dis 2003, 62:513–518.CrossRefPubMedGoogle Scholar
  36. 36.
    Felson DT, Anderson JJ, Naimark A, et al.: The prevalence of chondrocalcinosis in the elderly and its association with knee osteoarthritis: the Framingham Study. J Rheumatol 1989, 16:1241–1245.PubMedGoogle Scholar
  37. 37.
    Sanmarti R, Kanterewicz E, Pladevall M, et al.: Analysis of the association between chondrocalcinosis and osteoarthritis: a community based study. Ann Rheum Dis 1996, 55:30–33.CrossRefPubMedGoogle Scholar
  38. 38.
    Zhang Y, Terkeltaub R, Nevitt M, et al.: Lower prevalence of chondrocalcinosis in Chinese subjects in Beijing than in white subjects in the United States: the Beijing Osteoarthritis Study. Arthritis Rheum 2006, 54:3508–3512.CrossRefPubMedGoogle Scholar
  39. 39.
    Silcox DC, McCarty DJ Jr: Elevated inorganic pyrophosphate concentrations in synovial fluids in osteoarthritis and pseudogout. J Lab Clin Med 1974, 83:518–531.PubMedGoogle Scholar
  40. 40.
    Derfus B, Kranendonk S, Camacho N, et al.: Human osteoarthritic cartilage matrix vesicles generate both calcium pyrophosphate dihydrate and apatite in vitro. Calcif Tissue Int 1998, 63:258–262.CrossRefPubMedGoogle Scholar
  41. 41.
    Halverson PB: Calcium crystal-associated diseases. Curr Opin Rheumatol 1996, 8:259–261.CrossRefPubMedGoogle Scholar
  42. 42.
    Doherty M, Dieppe P: Clinical aspects of calcium pyrophosphate dihydrate crystal deposition. Rheum Dis Clin North Am 1988, 14:395–414.PubMedGoogle Scholar
  43. 43.
    Fam AG, Morava-Protzner I, Purcell C, et al.: Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis. Arthritis Rheum 1995, 38:201–210.CrossRefPubMedGoogle Scholar
  44. 44.
    Cheung HS, Story MT, McCarty DJ: Mitogenic effects of hydroxyapatite and calcium pyrophosphate dihydrate crystals on cultured mammalian cells. Arthritis Rheum 1984, 27:668–674.CrossRefPubMedGoogle Scholar
  45. 45.
    Hachicha M, Naccache PH, McColl SR: Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med 1995, 182:2019–2025.CrossRefPubMedGoogle Scholar
  46. 46.
    • Liu YZ, Jackson AP, Cosgrove SD: Contribution of calcium-containing crystals to cartilage degradation and synovial inflammation in osteoarthritis. Osteoarthr Cartil 2009, 17:1333–1340. This was a particularly valuable study investigating the effects of synthetic and native CPP crystals on human chondrocytes and synoviocytes.CrossRefPubMedGoogle Scholar
  47. 47.
    Whelan LC, Morgan MP, McCarthy GM: Basic calcium phosphate crystals as a unique therapeutic target in osteoarthritis. Front Biosci 2005, 10:530–541.CrossRefPubMedGoogle Scholar
  48. 48.
    •• Fuerst M, Bertrand J, Lammers L, et al.: Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum 2009, 60:2694–2703. This was a cartilage calcification study of 120 patients undergoing total knee replacement. It found BCP crystals in 100% of specimens and postulated the new idea of BCP calcification as an integral part of OA pathogenesis.CrossRefPubMedGoogle Scholar
  49. 49.
    Pritzker KP: Counterpoint: Hydroxyapatite crystal deposition is not intimately involved in the pathogenesis and progression of human osteoarthritis. Curr Rheumatol Rep 2009, 11:148–153.CrossRefPubMedGoogle Scholar
  50. 50.
    Oliviero F, Frallonardo P, Peruzzo L, et al.: Evidence of silicon dioxide crystals in synovial fluid of patients with osteoarthritis. J Rheumatol 2008, 35:1092–1095.PubMedGoogle Scholar
  51. 51.
    Grassi W, Meenagh G, Pascual E, Filippucci E: “Crystal clear”-sonographic assessment of gout and calcium pyrophosphate deposition disease. Semin Arthritis Rheum 2006, 36:197–202.CrossRefPubMedGoogle Scholar
  52. 52.
    Dalbeth N, McQueen FM: Use of imaging to evaluate gout and other crystal deposition disorders. Curr Opin Rheumatol 2009, 21:124–131.CrossRefPubMedGoogle Scholar
  53. 53.
    Schueller-Weidekamm C, Schueller G, Aringer M, et al.: Impact of sonography in gouty arthritis: comparison with conventional radiography, clinical examination, and laboratory findings. Eur J Radiol 2007, 62:437–443.CrossRefPubMedGoogle Scholar
  54. 54.
    Perez-Ruiz F, Martin I, Canteli B: Ultrasonographic measurement of tophi as an outcome measure for chronic gout. J Rheumatol 2007, 34:1888–1893.PubMedGoogle Scholar
  55. 55.
    • Thiele RG, Schlesinger N: Diagnosis of gout by ultrasound. Rheumatology (Oxford) 2007, 46:1116–1121. This article introduced specific diagnostic features for the detection of MSU crystals by ultrasonography.CrossRefGoogle Scholar
  56. 56.
    Puig JG, de Miguel E, Castillo MC, et al.: Asymptomatic hyperuricemia: impact of ultrasonography. Nucleosides Nucleotides Nucleic Acids 2008, 27:592–595.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Johannes Nowatzky
    • 1
    Email author
  • Rennie Howard
    • 1
  • Michael H. Pillinger
    • 1
  • Svetlana Krasnokutsky
    • 1
  1. 1.Department of Medicine, Division of RheumatologyNew York University Hospital for Joint DiseasesNew YorkUSA

Personalised recommendations