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Crystal arthropathies and osteoarthritis—where is the link?

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Abstract

Osteoarthritis (OA) is one of the leading causes of disability worldwide. As our understanding of OA progressively has moved from a purely mechanical “wear and tear” concept toward a complex multi-tissue condition in which inflammation plays a central role, the possible role of crystal-induced inflammation in OA incidence and progression may be relevant. In addition to gout, which affects 4% of the US population, basic calcium phosphate and calcium pyrophosphate deposition both may induce joint inflammation and may play a role in pain in OA. This narrative review article discusses the possible mechanisms underlying the associations between crystal-induced arthropathies and OA, and the important implications of these for clinical practice and future research.

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References

  1. Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum. 2008;59:1207–13.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil. 2014;95:986-995.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  3. GBD 2015 Disease and injury incidence and prevalence collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Lond Engl. 2016;388:1545–602.

    Article  Google Scholar 

  4. Abramson SB, Attur M, Yazici Y. Prospects for disease modification in osteoarthritis. Nat Clin Pract Rheumatol. 2006;2:304–12.

    Article  CAS  PubMed  Google Scholar 

  5. Crema MD, Felson DT, Roemer FW, Niu J, Marra MD, Zhang Y, et al. Peripatellar synovitis: comparison between non-contrast-enhanced and contrast-enhanced MRI and association with pain. MOST Study Osteoarthr Cartil. 2013;21:413–8.

    Article  CAS  Google Scholar 

  6. Roemer FW, Guermazi A, Felson DT, Niu J, Nevitt MC, Crema MD, et al. Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study. Ann Rheum Dis. 2011;70:1804–9.

    Article  PubMed  Google Scholar 

  7. Zhang Y, Nevitt M, Niu J, Lewis C, Torner J, Guermazi A, et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum. 2011;63:691–9.

    Article  PubMed  Google Scholar 

  8. Attur M, Krasnokutsky S, Statnikov A, Samuels J, Li Z, Friese O, et al. Low-grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers. Arthritis Rheumatol Hoboken NJ. 2015;67:2905–15.

    Article  CAS  Google Scholar 

  9. Krasnokutsky S, Belitskaya-Lévy I, Bencardino J, Samuels J, Attur M, Regatte R, et al. Quantitative magnetic resonance imaging evidence of synovial proliferation is associated with radiographic severity of knee osteoarthritis. Arthritis Rheum. 2011;63:2983–91.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthr Cartil. 2013;21:16–21.

    Article  CAS  Google Scholar 

  11. Neogi T, Krasnokutsky S, Pillinger MH. Urate and osteoarthritis: evidence for a reciprocal relationship. Joint Bone Spine. 2019;86:576–82.

    Article  CAS  PubMed  Google Scholar 

  12. Conway R, McCarthy GM. Calcium-containing crystals and osteoarthritis: an unhealthy alliance. Curr Rheumatol Rep. 2018;20:13.

    Article  PubMed  Google Scholar 

  13. Zell M, Aung T, Kaldas M, Rosenthal AK, Bai B, Liu T, et al. Calcium pyrophosphate crystal size and characteristics. Osteoarthr Cartil Open. 2021;3:100133.

    Article  PubMed  PubMed Central  Google Scholar 

  14. McCarthy GM, Dunne A. Calcium crystal deposition diseases - beyond gout. Nat Rev Rheumatol. 2018;14:592–602.

    Article  CAS  PubMed  Google Scholar 

  15. Rosenthal AK, Ryan LM. Nonpharmacologic and pharmacologic management of CPP crystal arthritis and BCP arthropathy and periarticular syndromes. Rheum Dis Clin North Am. 2014;40:343–56.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rosenthal AK. Basic calcium phosphate crystal-associated musculoskeletal syndromes: an update. Curr Opin Rheumatol. 2018;30:168–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McCarty DJ, Halverson PB, Carrera GF, Brewer BJ, Kozin F. “Milwaukee shoulder”–association of microspheroids containing hydroxyapatite crystals, active collagenase, and neutral protease with rotator cuff defects. I Clinical aspects. Arthritis Rheum. 1981;24:464–73.

    Article  CAS  PubMed  Google Scholar 

  18. Jones AC, Chuck AJ, Arie EA, Green DJ, Doherty M. Diseases associated with calcium pyrophosphate deposition disease. Semin Arthritis Rheum. 1992;22:188–202.

    Article  CAS  PubMed  Google Scholar 

  19. Doherty M, Watt I, Dieppe PA. Localised chondrocalcinosis in post-meniscectomy knees. Lancet Lond Engl. 1982;1:1207–10.

    Article  CAS  Google Scholar 

  20. Ramonda R, Musacchio E, Perissinotto E, Sartori L, Punzi L, Corti MC, et al. Prevalence of chondrocalcinosis in Italian subjects from northeastern Italy. The Pro.V.A. (PROgetto Veneto Anziani) study. Clin Exp Rheumatol. 2009;27:981–4.

    CAS  PubMed  Google Scholar 

  21. Felson DT, Anderson JJ, Naimark A, Kannel W, Meenan RF. The prevalence of chondrocalcinosis in the elderly and its association with knee osteoarthritis: the Framingham Study. J Rheumatol. 1989;16:1241–5.

    CAS  PubMed  Google Scholar 

  22. Guermazi A, Jarraya M, Lynch JA, Felson DT, Clancy M, Nevitt M, et al. Reliability of a new scoring system for intraarticular mineralization of the knee: Boston University Calcium Knee Score (BUCKS). Osteoarthr Cartil. 2020;28:802–10.

    Article  CAS  Google Scholar 

  23. Liew J, Guermazi A, Jarraya M, Wang N, Felson D, Lewis CE, et al. The Association of Radiographic Chondrocalcinosis with Localized Structural Outcomes in Knee OA: the multicenter osteoarthritis study [abstract]. Arthritis Rheumatol [Internet]. 2022;74. Available from: https://acrabstracts.org/abstract/the-association-of-radiographic-chondrocalcinosis-with-localized-structural-outcomes-in-knee-oa-the-multicenter-osteoarthritis-study/. Accessed September 17, 2022.

  24. Derfus BA, Kurian JB, Butler JJ, Daft LJ, Carrera GF, Ryan LM, et al. The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol. 2002;29:570–4.

    PubMed  Google Scholar 

  25. Nalbant S, Martinez JAM, Kitumnuaypong T, Clayburne G, Sieck M, Schumacher HR. Synovial fluid features and their relations to osteoarthritis severity: new findings from sequential studies. Osteoarthr Cartil. 2003;11:50–4.

    Article  CAS  Google Scholar 

  26. Fuerst M, Bertrand J, Lammers L, Dreier R, Echtermeyer F, Nitschke Y, et al. Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum. 2009;60:2694–703.

    Article  CAS  PubMed  Google Scholar 

  27. Meyer F, Dittmann A, Kornak U, Herbster M, Pap T, Lohmann CH, et al. Chondrocytes from osteoarthritic and chondrocalcinosis cartilage represent different phenotypes. Front Cell Dev Biol. 2021;9:622287.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Dieppe P, Swan A. Identification of crystals in synovial fluid. Ann Rheum Dis. 1999;58:261–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mitsuyama H, Healey RM, Terkeltaub RA, Coutts RD, Amiel D. Calcification of human articular knee cartilage is primarily an effect of aging rather than osteoarthritis. Osteoarthr Cartil. 2007;15:559–65.

    Article  CAS  Google Scholar 

  30. Ea H-K, Nguyen C, Bazin D, Bianchi A, Guicheux J, Reboul P, et al. Articular cartilage calcification in osteoarthritis: insights into crystal-induced stress. Arthritis Rheum. 2011;63:10–8.

    Article  CAS  PubMed  Google Scholar 

  31. Campillo-Gimenez L, Renaudin F, Jalabert M, Gras P, Gosset M, Rey C, et al. Inflammatory potential of four different phases of calcium pyrophosphate relies on NF-κB activation and MAPK pathways. Front Immunol. 2018;9:2248.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ea H-K, Chobaz V, Nguyen C, Nasi S, van Lent P, Daudon M, et al. Pathogenic role of basic calcium phosphate crystals in destructive arthropathies. PLoS One. 2013;8:e57352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Molloy ES, Morgan MP, Doherty GA, McDonnell B, O’Byrne J, Fitzgerald DJ, et al. Microsomal prostaglandin E2 synthase 1 expression in basic calcium phosphate crystal-stimulated fibroblasts: role of prostaglandin E2 and the EP4 receptor. Osteoarthr Cartil. 2009;17:686–92.

    Article  CAS  Google Scholar 

  34. McCarthy GM, Westfall PR, Masuda I, Christopherson PA, Cheung HS, Mitchell PG. Basic calcium phosphate crystals activate human osteoarthritic synovial fibroblasts and induce matrix metalloproteinase-13 (collagenase-3) in adult porcine articular chondrocytes. Ann Rheum Dis. 2001;60:399–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Grandjean-Laquerriere A, Tabary O, Jacquot J, Richard D, Frayssinet P, Guenounou M, et al. Involvement of toll-like receptor 4 in the inflammatory reaction induced by hydroxyapatite particles. Biomater. 2007;28:400–4.

    Article  CAS  Google Scholar 

  36. van der Kraan PM, van den Berg WB. Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration? Osteoarthr Cartil. 2012;20:223–32.

    Article  Google Scholar 

  37. Ea HK, Monceau V, Camors E, Cohen-Solal M, Charlemagne D, Lioté F. Annexin 5 overexpression increased articular chondrocyte apoptosis induced by basic calcium phosphate crystals. Ann Rheum Dis. 2008;67:1617–25.

    Article  CAS  PubMed  Google Scholar 

  38. Fam AG, Morava-Protzner I, Purcell C, Young BD, Bunting PS, Lewis AJ. Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis. Arthritis Rheum. 1995;38:201–10.

    Article  CAS  PubMed  Google Scholar 

  39. Neame RL. UK community prevalence of knee chondrocalcinosis: evidence that correlation with osteoarthritis is through a shared association with osteophyte. Ann Rheum Dis. 2003;62:513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Auw Yang KG, Raijmakers NJH, van Arkel ERA, Caron JJ, Rijk PC, Willems WJ, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthr Cartil. 2008;16:498–505.

    Article  CAS  Google Scholar 

  41. Schieker M, Conaghan PG, Mindeholm L, Praestgaard J, Solomon DH, Scotti C, et al. Effects of interleukin-1β inhibition on incident hip and knee replacement : exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2020;173:509–15.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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;63:3136–41.

    Article  PubMed  Google Scholar 

  43. Martillo MA, Nazzal L, Crittenden DB. The crystallization of monosodium urate. Curr Rheumatol Rep. 2014;16:400.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chhana A, Dalbeth N. The gouty tophus: a review. Curr Rheumatol Rep. 2015;17:19.

    Article  PubMed  Google Scholar 

  45. Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017;19:18.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Felson DT. Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther. 2009;11:203.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Simkin PA. The pathogenesis of podagra. Ann Intern Med. 1977;86:230–3.

    Article  CAS  PubMed  Google Scholar 

  48. Fam AG, Stein J, Rubenstein J. Gouty arthritis in nodal osteoarthritis. J Rheumatol. 1996;23:684–9.

    CAS  PubMed  Google Scholar 

  49. Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med. 2005;165:742–8.

    Article  PubMed  Google Scholar 

  50. Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM. Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee. Epidemiol Camb Mass. 1999;10:161–6.

    Article  CAS  Google Scholar 

  51. Muehleman C, Li J, Aigner T, Rappoport L, Mattson E, Hirschmugl C, et al. Association between crystals and cartilage degeneration in the ankle. J Rheumatol. 2008;35:1108–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier J-P, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7:33–42.

    Article  CAS  PubMed  Google Scholar 

  53. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.

    Article  CAS  PubMed  Google Scholar 

  54. Giamarellos-Bourboulis EJ, Mouktaroudi M, Bodar E, van der Ven J, Kullberg B-J, Netea MG, et al. Crystals of monosodium urate monohydrate enhance lipopolysaccharide-induced release of interleukin 1 beta by mononuclear cells through a caspase 1-mediated process. Ann Rheum Dis. 2009;68:273–8.

    Article  CAS  PubMed  Google Scholar 

  55. Zengini E, Hatzikotoulas K, Tachmazidou I, Steinberg J, Hartwig FP, Southam L, et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat Genet. 2018;50:549–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Major TJ, Dalbeth N, Stahl EA, Merriman TR. An update on the genetics of hyperuricaemia and gout. Nat Rev Rheumatol. 2018;14:341–53.

    Article  CAS  PubMed  Google Scholar 

  57. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425:516–21.

    Article  CAS  PubMed  Google Scholar 

  58. Lai J-H, Luo S-F, Hung L-F, Huang C-Y, Lien S-B, Lin L-C, et al. Physiological concentrations of soluble uric acid are chondroprotective and anti-inflammatory. Sci Rep. 2017;7:2359.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Accart N, Dawson J, Obrecht M, Lambert C, Flueckiger M, Kreider J, et al. Degenerative joint disease induced by repeated intra-articular injections of monosodium urate crystals in rats as investigated by translational imaging. Sci Rep. 2022;12:157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Roddy E, Zhang W, Doherty M. Are joints affected by gout also affected by osteoarthritis? Ann Rheum Dis. 2007;66:1374–7.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sun Y, Brenner H, Sauerland S, Günther KP, Puhl W, Stürmer T. Serum uric acid and patterns of radiographic osteoarthritis–the Ulm Osteoarthritis Study. Scand J Rheumatol. 2000;29:380–6.

    Article  CAS  PubMed  Google Scholar 

  62. Roddy E, Zhang W, Doherty M. Gout and nodal osteoarthritis: a case-control study. Rheumatol. 2008;47:732–3.

    Article  CAS  Google Scholar 

  63. Kuo C-F, Chou I-J, See L-C, Chen J-S, Yu K-H, Luo S-F, et al. Urate-lowering treatment and risk of total joint replacement in patients with gout. Rheumatol Oxf Engl. 2018;57:2129–39.

    Article  Google Scholar 

  64. Kuo C-F, Grainge MJ, Mallen C, Zhang W, Doherty M. Comorbidities in patients with gout prior to and following diagnosis: case-control study. Ann Rheum Dis. 2016;75:210–7.

    Article  PubMed  Google Scholar 

  65. Dalbeth N, Aati O, Kalluru R, Gamble GD, Horne A, Doyle AJ, et al. Relationship between structural joint damage and urate deposition in gout: a plain radiography and dual-energy CT study. Ann Rheum Dis. 2015;74:1030–6.

    Article  CAS  PubMed  Google Scholar 

  66. Kravchenko D, Karakostas P, Kuetting D, Meyer C, Brossart P, Behning C, et al. The role of dual energy computed tomography in the differentiation of acute gout flares and acute calcium pyrophosphate crystal arthritis. Clin Rheumatol. 2022;41:223–33.

    Article  PubMed  Google Scholar 

  67. Baum T, Joseph GB, Karampinos DC, Jungmann PM, Link TM, Bauer JS. Cartilage and meniscal T2 relaxation time as non-invasive biomarker for knee osteoarthritis and cartilage repair procedures. Osteoarthr Cartil. 2013;21:1474–84.

    Article  CAS  Google Scholar 

  68. Le J, Peng Q, Sperling K. Biochemical magnetic resonance imaging of knee articular cartilage: T1rho and T2 mapping as cartilage degeneration biomarkers. Ann N Y Acad Sci. 2016;1383:34–42.

    Article  PubMed  Google Scholar 

  69. Zhu J, Hu N, Hou J, Liang X, Wang Y, Zhang H, et al. T1rho mapping of cartilage and menisci in patients with hyperuricaemia at 3 T: a preliminary study. Clin Radiol. 2021;76:710.e1-710.e8.

    Article  CAS  PubMed  Google Scholar 

  70. Hu N, Zhu J, Liang X, Wang Y, Guan J, Wen W, et al. T2 MRI at 3T of cartilage and menisci in patients with hyperuricemia: initial findings. Skeletal Radiol. 2022;51:607–18.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, YAW 6044, Boston, MA, 02114, USA

    Mohamed Jarraya

  2. Department of Radiology, Boston University School of Medicine, Boston, MA, USA

    Frank Roemer & Ali Guermazi

  3. Department of Radiology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany

    Frank Roemer

  4. Division of Rheumatology, The University of Arizona, Tucson, AZ, USA

    C. Kent Kwoh

  5. Department of Radiology, VA Boston Healthcare System, West Roxbury, MA, USA

    Ali Guermazi

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  1. Mohamed Jarraya
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Correspondence to Mohamed Jarraya.

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Conflict of interest

AG: received consultancy fees from Pfizer, Novartis, MerckSerono, TissueGene, AstraZeneca, and Regeneron. He is a shareholder of Boston Imaging Core Lab., LLC. FWR: Consultant to Calibr and Grünenthal. He is a shareholder of Boston Imaging Core Lab., LLC. CKK has received consultancy fees from Thuasne, Regeneron, Novartis, Kolon Tissue Gene, Taiwan Liposome, Amzell AZ, LG Chem, Express Scripts, and has received grants from Lilly, Pfizer GSK, Cumberland.

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Jarraya, M., Roemer, F., Kwoh, C.K. et al. Crystal arthropathies and osteoarthritis—where is the link?. Skeletal Radiol 52, 2037–2043 (2023). https://doi.org/10.1007/s00256-022-04246-8

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