Skip to main content
SpringerLink
Log in

The role of crystals in articular tissue degeneration

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

The deposition of calcium-containing crystals in articular tissues is probably an underrecognized event. Clinical observations indicate that exaggerated and uniquely distributed cartilage degeneration is associated with these deposits. Perhaps the most compelling argument favoring a role for crystals in causing osteoarthritis stems from their in vitro effects on articular tissues. In this short review, we will discuss the fact that crystals can cause the degeneration of articular tissues in 2 separate pathways. In the "Direct" pathway, crystals directly induce fibroblast-like synoviocytes to proliferate and produce metalloproteinases and prostaglandins. The other "Paracrine pathway" involves the interaction between crystals and macrophages/monocytes, which leads to synthesis and release of cytokines that can reinforce the action of crystals on synoviocytes and induce chondrocytes to secrete enzymes, eventually causing the degeneration of articular tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Halverson PB, Greene A, Cheung HS: Intracellular calcium responses to BCP crystals in fibroblasts. Osteoarthritis Cartilage 1998, 6:324–329.

    Article  PubMed  CAS  Google Scholar 

  2. Ryan LM, McCarty DJ: Calcium pyrophosphate crystal deposition disease, pseudogout, and articular chondrocalcinosis, arthritis and allied conditions In Edited by Koopman WJ. Baltimore, Williams and Wilkins; 1997:2103.

    Google Scholar 

  3. Gibilisco PA, Schumacher HR, Hollander JL, Soper KA: Synovial fluid crystals in osteoarthritis. Arthritis Rheum 1985, 28:511–51 5.

    Article  PubMed  CAS  Google Scholar 

  4. Klashman DJ, Moreland LW, Ike RW, Kalunian KC: Occult presence of CPPD crystals in patients undergoing arthro-scopic knee irrigation for refractory pain related to OA. Arthritis Rheum 1994, 37(Abstract):S240.

    Google Scholar 

  5. Swan A, Chapman B, Heap P, et al.: Submicroscopic crystals in osteoarthritic synovial fluids. Ann Rheum Dis 1994, 53:467–470.

    Article  PubMed  CAS  Google Scholar 

  6. Ledingham J, Regan M, Jones A, Doherty M: Factors affecting radiographic progression of knee osteoarthritis. Ann Rheum Dis 1995, 54:53–58.

    PubMed  CAS  Google Scholar 

  7. Zitnan D, Sitaj S: Natural course of articular chondrocalci-nosis. Arthritis Rheum 1976, 19:363–390.

    Article  PubMed  Google Scholar 

  8. Carroll G, McCappin S, Bell M, et al.: Comparison of keratan sul-phate concentrations and the size distribution of proteoglycans in the synovial fluid of patients with osteoarthritis and pyro-phosphate arthropathy. Rheumatol Int 1991, 11:63–68.

    Article  PubMed  CAS  Google Scholar 

  9. Lohmander LS, Hoerrner LA, Lark MW: Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis. Arthritis Rheum 1993, 36:181–189.

    Article  PubMed  CAS  Google Scholar 

  10. Saxne T, Heinegard D, Wollheim FA: Cartilage proteoglycans in synovial fluid and serum in patients with inflammatory joint disease. Arthritis Rheum 1987, 30:972–979.

    Article  PubMed  CAS  Google Scholar 

  11. Cheung HS, Ryan LM: Role of crystal deposition in matrix degradation. In Joint Cartilage Degradation: Basic and Clinical Aspects. Edited by Woessner FJ, Howell DS. New York,Marcel Dekker, Inc; 1995:209.

    Google Scholar 

  12. Rothenberg RJ: Modulation of prostaglandin E2 synthesis in rabbit synoviocytes. Arthritis Rheum 1987, 30:266–274.

    Article  PubMed  CAS  Google Scholar 

  13. Rothenberg RJ, Cheung H: Rabbit synoviocyte inositol phos-pholipid metabolism is stimulated by hydroxyapatite crystals. Am J Physiol. 1988, 254:C554-C559.

    PubMed  CAS  Google Scholar 

  14. Cheung HS, Sallis JD, Mitchell PG, Struve JA: Inhibition of basic calcium phosphate crystal-induced mitogenesis by phosphocitrate. Biochem Biophys Res Comm 1990, 171:20–25.

    Article  PubMed  CAS  Google Scholar 

  15. McCarthy GM, Augustine JA, Baldwin AS, et al.: Molecular mechanism of BCP crystal-induced activation of human fibroblasts: role of nuclear bB, activator protein 1, and protein kinase C. J Biol Chem 1998, 273:35161–35169. BCP crystal-induced cell activation is associated with NF-kB induction in Balb-c/3T3 and HF and PKC activation and AP-1 induction in human fibroblasts.

    Article  PubMed  CAS  Google Scholar 

  16. McCarthy GM, Macius AM, Christopherson PA, et al.: Basic calcium phosphate crystals induce synthesis and secretion of 92 kDa gelatinase (gelatinaseB/matrix metalloprotease 9) in human fibroblasts. Ann Rheum Dis 1998, 57:56–60.

    Article  PubMed  CAS  Google Scholar 

  17. McCarthy GM, Mitchell PG, Struve JA, Cheung HS: Basic calcium phosphate crystals cause coordinate induction and secretion of collagenase and stromelysin. J Cell Physiol 1992, 153:140–146.

    Article  PubMed  CAS  Google Scholar 

  18. Cheung HS, Van Wyk JJ, Russell WE, McCarty DJ: Mitogenic activity of hydroxyapatite: Requirement for somatomedin. C J Cell Physiol 1986, 128:143–148.

    Article  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. Brogley M, Cruz M, Cheung HS: Basic calcium phosphate crys-tal induction of MMP-1 and MMP-3 expression is dependent upon a p42/44 mitogen-activated protein kinase signal trans-duction pathway. J Cell Physiol 1999, 180:215–224. Demonstrate that the p42/44 MAPK pathway is the important signal transduction pathway of crystal-induced metalloproteinase-1 and -3 synthesis.

    Article  PubMed  CAS  Google Scholar 

  21. Nair D, Misra RP, Sallis JD, Cheung HS: Phosphocitrate inhib-its a basic calcium phosphate and calcium pyrophosphate dihydrate crystal-induced mitogen-activated protein kinase cascade signal transduction pathway. J Biol Chem 1997, 272:18920–18925. Demonstrated for the first time that p42 and p44 mitogen-activated protein [MAP] kinase pathway is the mediator of crystal-induced signals to the nucleus.

    Article  PubMed  CAS  Google Scholar 

  22. Angel P, Karin M: The role of jun, fos and the AP-1 complex in cell-proliferation and transformation. Biochem Biophys Acta 1991, 1072:129–157.

    PubMed  CAS  Google Scholar 

  23. Mitchell PG, Pledger JW, Cheung HS: Molecular mechanism of basic calcium phosphate crystal-induced mitogenesis. J Biol Chem. 1989, 264:14071–14077.

    PubMed  CAS  Google Scholar 

  24. Mitchell PG, Struve JM, McCarthy GM, Cheung HS: Basic calcium phosphate crystals stimulate cell proliferation and collagenase and stromelysin messenger RNA accumulation in cultured adult porcine chondrocytes. Arthritis Rheum 1992, 35:343–350.

    Article  PubMed  CAS  Google Scholar 

  25. Halverson PB, McCarty DJ: Basic calcium phosphate (apatite, octacalcium phosphate, tricalcium phosphate) crystal depo-sition disease; calcinosis, arthritis and allied conditions. Edited by Koopman WJ. Baltimore, Williams and Wilkins; 1997:2127.

    Google Scholar 

  26. Sheng M, McFadden G, Greenber ME: The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 1990, 4:571–582.

    Article  PubMed  CAS  Google Scholar 

  27. Sheng M, Thompson MA, Greenberg ME: CREB: A Ca2+-regu-lated transcription factor phosphorylated by calmodulin-dependent kinases. Science 1991, 252:1427–1430.

    Article  PubMed  CAS  Google Scholar 

  28. Karin M: The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 1995, 270:16483–16486.

    PubMed  CAS  Google Scholar 

  29. Karin M, Liu Z, Zandi E: AP-1 function and regulation. Curr Opin Cell Biol 1997, 9:240–246.

    Article  PubMed  CAS  Google Scholar 

  30. Benbow U, Brinckerhoff CE: The AP-1 site and MMP gene regulation: what is all the fuss about? Matrix Biol 1997, 15:519–526.

    Article  PubMed  CAS  Google Scholar 

  31. Malawista SE, Duff GW, Atkins E, et al.: Crystal-induced endo-genous pyrogen production: a further look at gouty inflam-mation. Arthritis Rheum 1985, 28:1039–1046.

    Article  PubMed  CAS  Google Scholar 

  32. Dayer JM, Evequoz V, Zavadil-Grob C, et al.: Effect of synthetic CPPD and hydroxyapatite crystals on the interaction o human blood mononuclear cells with chondrocytes, synovial cells, and fibroblasts. Arthritis Rheum. 1987, 30:1372–1381.

    Article  PubMed  CAS  Google Scholar 

  33. Fava R, Olsen N, Keski-Oja J, et al.: Active and latent forms of TGF-ß activity in synovial effusions. J Exp Med 1987, 169:291–296.

    Article  Google Scholar 

  34. Rosenthal AK, Rosier TA, Ryan LM: TGF-b levels in synovial fluid. Arthritis Rheum 1993, 36:S162.

    Article  Google Scholar 

  35. Rosenthal AK, Cheung HS, Ryan LM: Transforming growth factor B1 stimulates inorganic pyrophosphate elaboration by porcine cartilage. Arthritis Rheum 1991, 34:904–911.

    Article  PubMed  CAS  Google Scholar 

  36. Nagase M, Baker DG, Schumacher HR: Prolonged inflam-matory reactions induced by artificial ceramics in the rat air pouch model. J Rheumatol 1988, 15:1334–1338.

    PubMed  CAS  Google Scholar 

  37. Guerne P, Terkeltaub R, Zuraw B, Lotz M: Inflammatory micro-crystals stimulate interleukin-6 production and secretion by human monocytes and synoviocytes. Arthritis Rheum 1989, 32:1443–1452.

    Article  PubMed  CAS  Google Scholar 

  38. Howard JE: Studies on urinary stone formation: a saga of clinical investigation. John Hopkins Med J 1976, 139:239–252.

    CAS  Google Scholar 

  39. Tew WP, Malis CD, Howard JE, Lehninger AL: Phosphocitrate inhibits mitochondrial and cytosolic accumulation of calcium in kidney cells in vivo. Proc Natl Acad Sci USA 1981, 78:5528–5532.

    Article  PubMed  CAS  Google Scholar 

  40. Cheung HS, Sallis JD, Struve JA: Specific inhibition of basic calcium phosphate and calcium pyrophosphate crystal-induction of metalloproteinase synthesis by phosphocitrate. Biochem Biophys Acta 1996, 1315:105–111.

    PubMed  Google Scholar 

  41. Cheung HS, Mitchell P, Pledger WJ: Activation of proto-oncogenes by BCP crystals: Effect of beta-interferon. Cancer Res 1989, 49:134–139.

    PubMed  CAS  Google Scholar 

  42. Krug HE, Mahowald ML, Halverson PB, et al.: Phosphocitrate prevents disease progression in murine prgressive ankylosis. Arthritis Rheum 1993, 36:1603–1611. Demonstrated for the first time that phosphocitrate inhibits disease progression when given before disease is established in murine progressive ankylosis—an animal model of BCP crystal deposition disease.

    Article  PubMed  CAS  Google Scholar 

  43. Cheung HS, Kurup IV, Sallis JD, Ryan LM: Inhibition of calcium pyrophosphate dihydrate crystal formation in articu-lar cartilage vesicles and cartilage by phosphocitrate. J Biol Chem 1996, 271:28082–28085. Demonstrated for the first time that PC can block both BCP and CPPD crystal formation in matrix vesicle and an intact cartilage in an in vitro model of chondrocalcinosis.

    Article  PubMed  CAS  Google Scholar 

  44. Cheung HS, Ryan LM: Phosphocitrate blocks nitric oxide-induced calcification. OA Cart 1999, 7:409–412.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology and Immunology, Department of Medicine, University of Miami School of Medicine, 1201 NW 16 St. (11GRC), Miami, FL

    Herman S. Cheung PhD (Professor of Medicine)

  2. Geriatric Research, Education, and Clinical Center, VA Medical Center, 1201 NW 16 St. (11GRC), Miami, FL

    Herman S. Cheung PhD (Professor of Medicine)

Authors
  1. Herman S. Cheung PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheung, H.S. The role of crystals in articular tissue degeneration. Curr Rheumatol Rep 1, 128–131 (1999). https://doi.org/10.1007/s11926-999-0009-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-999-0009-1

Keywords

Search

Navigation