Skip to main content
Log in

Hydroxyapatite deposition disease of the joint

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Basic calcium phosphate (BCP) crystals include partially carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate. They may form deposits, which are frequently asymptomatic but may give rise to a number of clinical syndromes including calcific periarthritis, Milwaukee shoulder syndrome, and osteoarthritis, in and around joints. Recent data suggest that magnesium whitlockite, another form of BCP, may play a pathologic role in arthritis. Data from the past year have provided further understanding of the mechanisms by which BCP crystals induce inflammation and degeneration. There remains no specific treatment to modify the effects of BCP crystals. Although potential drugs are being identified as the complex pathophysiology of BCP crystals is unraveled, much work remains to be done in order to translate research advances to date into tangible clinical benefits.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Bosworth BM: Calcium deposits in the shoulder and subacromial bursitis: a survey of 12,222 shoulders. JAMA 1941, 116:2477–2482.

    Google Scholar 

  2. Ebenbichler G, Erdogmus C, Resch K, et al.: Ultrasound therapy for calcific tendinitis of the shoulder. N Engl J Med 1999, 340:1533–1538.

    Article  PubMed  CAS  Google Scholar 

  3. Dieppe PA, Crocker PR, Corke CF, et al.: Synovial fluid crystals. Q J Med 1979, 192:533–553.

    Google Scholar 

  4. Gibilisco PA, Schumacher HR, Hollander JL, Soper KA: Synovial fluid crystals in osteoarthritis. Arthritis Rheum 1985, 28:511–515.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  6. Halverson PB, McCarty DJ: Patterns of radiographic abnormalities associated with basic calcium phosphate and calcium pyrophosphate crystal deposition in the knee. Ann Rheum Dis 1986, 45:603–605.

    Article  PubMed  CAS  Google Scholar 

  7. Carroll GJ, Stuart RA, Armstrong JA: Hydroxyapatite crystals are a frequent finding in osteoarthritic synovial fluid, but are not related to increased concentrations of keratan sulfate or interleukin 1-beta. J Rheumatol 1991, 18:861–866.

    PubMed  CAS  Google Scholar 

  8. McCarty DJ, Halverson PB, Carrera GF: Milwaukee shoulder: association of microspheroids containing hydroxyapatite crystals, active collagenase, and neutral protease with rotator cuff defects, clinical aspects. Arthritis Rheum 1981, 24:464–473.

    Article  PubMed  CAS  Google Scholar 

  9. McCarty D, Swanson A, Ehrhart R: Hemorrhagic rupture of the shoulder. J Rheumatol 1994, 21:1134–1137.

    PubMed  CAS  Google Scholar 

  10. Pons-Estel BA, Gimenez C, Sacnun M, et al.: Familial osteoarthritis and Milwaukee shoulder associated with calcium pyrophosphate and apatite crystal deposition. J Rheumatol 2000, 27:471–480. This paper described a kindred with OA and MSS with peri- and intraarticular calcification. A number of potential candidate loci were ruled out as being responsible for the phenotype described.

    PubMed  CAS  Google Scholar 

  11. Yamagami T, Kawano N, Nakano H: Calcification of the cervical ligamentum flavum: case report. Neurol Med Chir 2000, 40:234–238.

    Article  CAS  Google Scholar 

  12. Tadjalli HE, Kessler FB, Abrams J: Tumoral calcinosis of the triangular fibrocartilage complex: case report. J Hand Surg 1997, 22:350–353.

    Article  CAS  Google Scholar 

  13. Rosenthal A, Mandel N: Identification of crystals in synovial fluids and joint tissues. Curr Rheumatol Rep 2001, 3:11–16. A thorough review of the techniques used in crystal identification.

    PubMed  CAS  Google Scholar 

  14. Amer H, Swan A, Dieppe P: The utilization of synovial fluid analysis in the UK. Rheumatology 2001, 40:1060–1063.

    Article  PubMed  CAS  Google Scholar 

  15. Gordon C, Swan A, Dieppe P: Detection of crystals in synovial fluids by light microscopy: sensitivity and reliability. Ann Rheum Dis 1989, 48:737–742.

    PubMed  CAS  Google Scholar 

  16. Halverson PB, Cheung HS, McCarty DJ, et al.: Milwaukee shoulder: association of microspheroids containing hydroxyapatite crystals, active collagenase and neutral protease with rotator cuff defects, II: synovial fluid studies. Arthritis Rheum 1981, 24:474–483.

    Article  PubMed  CAS  Google Scholar 

  17. Mandel G, Mandel N: Analysis of stones. In Kidney Stones: Medical and Surgical Management. Edited by Coe FL, Favus MJ, Pak CYC, et al. Philadelphia: Lippincott-Raven; 1986:323–335.

    Google Scholar 

  18. Hamada J, Ono W, Tamai K, et al.: Analysis of calcium deposits in calcific periarthritis. J Rheumatol 2001, 28:809–813. This paper suggests that apatite is present in BCP deposits in the form of carbonate apatite.

    PubMed  CAS  Google Scholar 

  19. Sarker K, Uhthoff HK: Ultrastructural localization of calcium in calcifying tendinitis. Arch Pathol Lab Med 1978, 102:266–269.

    Google Scholar 

  20. Kajander EO, Çiftçioglu AN: Nanobacteria: an alternative mechanism for pathogenic intra- and extracellular calcification and stone formation. Proc Natl Acad Sci U S A 1998, 95:8274–8279.

    Article  PubMed  CAS  Google Scholar 

  21. Cisar JO, Xu DQ, Thomson J, et al.: An alternative interpretation of nanobacteria-induced biomineralisation. Proc Natl Acad Sci U S A 2000, 97:11511–11515.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Dieppe P, Doherty M, Papadimitriou GM: Inflammatory responses to intradermal crystals in healthy volunteers and patients with rheumatic diseases. Rheumatol Int 1982, 2:55–58.

    Article  PubMed  CAS  Google Scholar 

  24. Terkeltaub RA, Ginsberg MH: The inflammatory reaction to crystals. Rheum Dis Clin North Am 1988, 14:353–364.

    PubMed  CAS  Google Scholar 

  25. Hajeroussan VJ, Short CL: Familial calcific periarthritis. Ann Rheum Dis 1983, 42:469–470.

    Google Scholar 

  26. Kranendonk S, Ryan L, Buday M, et al.: Human osteoarthritic vesicles generate both monoclinic calcium pyrophosphate dihydrate and apatite crystals in vitro. J Bone Joint Surg 1994, 18:502–503.

    Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. Derfus B, Kurtin S, Camacho N, et al.: Comparison of matrix vesicles from normal and osteoarthritic human articular cartilage. Connect Tissue Res 1996, 35:337–342.

    PubMed  CAS  Google Scholar 

  29. Karpouzas GA, Terkeltaub RA: New developments in the pathogenesis of articular cartilage calcification. Curr Rheumatol Rep 1999, 1:121–127.

    Article  PubMed  CAS  Google Scholar 

  30. Ho A, Johnson M, Kingsley D: Role of the mouse ank gene in control of tissue calcification and arthritis. Science 2000, 289:265–269.

    Article  PubMed  CAS  Google Scholar 

  31. Scotchford CA, Ali SY: Magnesium whitlockite deposition in articular cartilage: a study of 80 specimens from 70 patients. Ann Rheum Dis 1995, 54:339–344.

    PubMed  CAS  Google Scholar 

  32. Ryan L, Cheung H, LeGeros R, et al.: Cellular responses to whitlockite. Calcif Tiss Int 1999, 65:374–377. This paper explores the potentially pathologic and biologic effects of whitlockite.

    Article  CAS  Google Scholar 

  33. McCarthy G, Westfall P, Masuda I, et al.: Basic calcium phosphate crystals activate human osteoarthritis synovial fibroblasts and induce matrix metalloproteinase-13 (collagenase-3) in adult porcine articular chondrocytes. Ann Rheum Dis 2001, 60:399–406. This paper reports for the first time that BCP crystals induce mitogenesis in human synovial fibroblasts and MMP-13 production from chondrocytes in vitro.

    Article  PubMed  CAS  Google Scholar 

  34. 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 

  35. McCarthy GM, Augustine JA, Baldwin AS, et al.: Molecular mechanism of basic calcium phosphate crystal-induced activation of human fibroblasts: role of nuclear factor kB, activator protein 1 and protein kinase C. J Biol Chem 1998, 273:35161–35169.

    Article  PubMed  CAS  Google Scholar 

  36. Nair D, Misra RP, Sallis JD, Cheung HS: Phosphocitrate inhibits 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.

    Article  PubMed  CAS  Google Scholar 

  37. McCarthy GM, Mitchell PG, Struve JS, Cheung HS: Basic calcium phosphate crystals cause co-ordinate induction and secretion of collagenase and stromelysin. J Cell Physiol 1992, 153:140–146.

    Article  PubMed  CAS  Google Scholar 

  38. Bai G, Howell DS, Howard GA, et al.: Basic calcium phosphate crystals upregulate metalloproteinases but downregulate tissue inhibitor of metalloproteinase-1 and -2 in human fibroblasts. Osteoarthritis Cartilage 2001, 9:416–422. This paper shows that BCP crystals upregulate MMPs and also downregulate their natural inhibitors—the tissue inhibitors of metalloproteinases.

    Article  PubMed  CAS  Google Scholar 

  39. Dean DD, Martel-Pelletier J, Pelletier JP, et al.: Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Invest 1989, 84:678–685.

    PubMed  CAS  Google Scholar 

  40. Martel-Pelletier J, McCollum R, Fujimoto N, et al.: Excess of MMP over TIMP may contribute to cartilage degradation in OA and RA. Lab Invest 1994, 70:807–815.

    PubMed  CAS  Google Scholar 

  41. McCarthy GM, Cheung HS, Abel SM, et al.: Basic calcium phosphate crystal-induced collagenase production: role of intracellular crystal dissolution. Osteoarthritis Cartilage 1998, 6:205–213.

    Article  PubMed  CAS  Google Scholar 

  42. Cheung HS, McCarty DJ: Mitogenesis induced by calcium containing crystals: role of intracellular dissolution. Exp Cell Res 1985, 157:63–70.

    Article  PubMed  CAS  Google Scholar 

  43. Borkowf A, Cheung HS, McCarty DJ: Endocytosis is required for the mitogenic effect of basic calcium phosphate crystals. Calcif Tissue Int 1987, 40:173–176.

    Article  PubMed  CAS  Google Scholar 

  44. Morgan M, Fitzgerald D, McCarthy C, McCarthy G: Basic calcium phosphate crystals cause increased production of prostaglandin E2 by induction of both cyclooxygenase-1 and cyclooxygenase-2 in human fibroblasts. Arthritis Rheum 2000, 43:S281.

    Article  Google Scholar 

  45. Ryan L, Kurup I, Cheung HS: Transduction mechanisms of porcine chondrocyte inorganic pyrophosphate elaboration. Arthritis Rheum 1999, 42:555–560.

    Article  PubMed  CAS  Google Scholar 

  46. Williams G, Sallis J: Structure-activity relationship of inhibitors of hydroxyapatite formation. Biochem J 1979, 184:181–184.

    PubMed  CAS  Google Scholar 

  47. McCarthy GM, Cheung HS: The role of cyclic-3′, ′-adenosine monophosphate in prostaglandin-mediated inhibition of basic calcium phosphate crystal-induced mitogenesis and collagenase induction in cultured human fibroblasts. Biochim Biophys Acta 1994, 1226:97–104.

    PubMed  CAS  Google Scholar 

  48. Hamilton JA, McCarthy GM, Whitty G: Inflammatory microcrystals induce murine macrophage survival and DNA synthesis. Arthritis Res 2001, 3:242–246. This paper demonstrates the potential for BCP crystals to contribute to synovial hyperplasia via macrophage mitogenesis.

    Article  PubMed  CAS  Google Scholar 

  49. Meng ZH, Hudson AP, Schumacher R, et al.: Monosodium urate, hydroxyapatite and calcium pyrophosphate crystals induce tumor necrosis factor-a expression in a mononuclear cell line. J Rheumatol 1997, 24:2385–2388.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  51. Cheung H, Sallis J, Mitchell P, Struve J: Inhibition of basic calcium phosphate crystal-induced mitogenesis by phosphocitrate. Biochem Biophys Res Commun 1990, 171:20–25.

    Article  PubMed  CAS  Google Scholar 

  52. Cheung H, Sallis J, Struve J: Specific inhibition of basic calcium phosphate and calcium pyrophosphate crystalinduction of metalloproteinase synthesis by phosphocitrate. Biochim Biophys Acta 1996, 1315:10.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molloy, E.S., McCarthy, G.M. Hydroxyapatite deposition disease of the joint. Curr Rheumatol Rep 5, 215–221 (2003). https://doi.org/10.1007/s11926-003-0070-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-003-0070-0

Keywords

Navigation