Current Rheumatology Reports

, Volume 14, Issue 2, pp 155–160

Genetics and Mechanisms of Crystal Deposition in Calcium Pyrophosphate Deposition Disease



Calcium pyrophosphate deposition (CPPD) disease (common in older adults) can be asymptomatic, associated with osteoarthritis, or can present as acute/chronic inflammatory arthritis. Due to the phenotypic complexity of CPPD, the European League Against Rheumatism (EULAR) recently made recommendations on terminology, diagnosis, and management based on available research evidence and expert consensus. There are no disease-modifying treatments for CPPD disease, and therapy remains nonspecific with the use of anti-inflammatory and analgesic drugs. For years, it has been known that inorganic phosphate and pyrophosphate regulate the formation of CPP or hydroxyapatite crystals. The discovery of ANKH (human homologue of progressive ankylosis) mutations in familial CPPD disease confirmed the importance of phosphate/pyrophosphate homeostasis in CPPD, with ANKH being a regulator of inorganic pyrophosphate transport. Despite progress in our understanding of the function of ANKH, much remains to be investigated. This review summarizes the genetic basis of this disease and focuses on the challenges of research in this area.


Calcium pyrophosphate deposition (CPPD) Chondrocalcinosis (CC) Human homologue of progressive ankylosis (ANKH) Familial disease Mutations Animal models Tissue nonspecific alkaline phosphatase (TNAP) Sodium/phosphate co-transporter PiT-1 Genetics Mechanisms Crystal deposition Crystal arthritis 


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

  1. 1.
    McCarty D, Kohn N, Faires J. The significance of calcium pyrophosphate crystals in the synovial fluid of arthritic patients. 1. Clinical aspects. Ann Intern Med. 1962;56:711–37.Google Scholar
  2. 2.
    •• Zhang W, Doherty M, Bardin T et al. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011; 70:563–70. Based on expert consensus and research evidence, this is the first attempt to streamline the terminology for CPPD and recommend criteria for its diagnosis. A research agenda was also suggested for guiding and improving the evidence base to facilitate diagnosis. PubMedCrossRefGoogle Scholar
  3. 3.
    •• Zhang W, Doherty M, Pascual E, et al. EULAR recommendations for calcium pyrophosphate deposition. Part II: Management. Ann Rheum Dis. 2011; 70:571–5. Due to the lack of specific treatment to modulate CPPD formation/dissolution, recommendations for CPPD management were restricted to symptomatic control. PubMedCrossRefGoogle Scholar
  4. 4.
    • Pascual E, Sivera F, Andrés M. Synovial fluid analysis for crystals. Curr Opin Rheumatol. 2011; 23:161–9. This is a recent and critical review on acquiring/perfecting the technique to identify crystals (both CPP and monosodium urate) in SF. PubMedGoogle Scholar
  5. 5.
    Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dehydrate crystal deposition disease. Rheumatol. 2009;48:711–5.CrossRefGoogle Scholar
  6. 6.
    Baldwin CT, Farrer LA, Adair R, et al. Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q. Am J Hum Genet. 1995;56:692–7.PubMedGoogle Scholar
  7. 7.
    Andrew LJ, Brancolini V. Serrano de la Pena L et al.: Refinement of the chromosome 5p locus for familial calcium pyrophosphate dehydrate deposition disease. Am J Hum Genet. 1999;64:136–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank gene in control of tissue calcification and arthritis. Science. 2000;289:265–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Pendleton A, Johnson MD, Hughes A, et al. Mutations in ANKH caused chondrocalcinosis. Am J Hum Genet. 2001;71:933–40.CrossRefGoogle Scholar
  10. 10.
    Williams CJ, Zhang Y, Timms A, et al. Autosomal dominant familial calcium pyrophosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH. Am J Hum Genet. 2002;71:985–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Williams CJ, Pendleton A, Bonavita G, et al. Mutations in the amino terminus of ANKH in two US families with calcium pyrophosphate dehydrate crystal deposition disease. Arthritis Rheum. 2003;48:2627–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang Y, Johnson K, Russell FF, et al. Association of sporadic chondrocalcinosis with a 4-basepair G- to A- transition in the 5′-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate. Arthritis Rheum. 2005;52:1110–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Reichenberger E, Triziani V, Satanabe S, et al. Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Am J Hum Genet. 2001;68:1321–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Nürnberg P, Thiele H, Chandler D, et al. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet. 2001;28:37–41.PubMedGoogle Scholar
  15. 15.
    Baynam G, Goldblatt J, Schofield L. Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation. Am J Med Genet. 2009; PartA 149A:1331–1333.Google Scholar
  16. 16.
    •• Abhishek A, Doherty M. Pathophysiology of articular chondrocalcinosis—role of ANKH. Nat Rev Rheumatol. 2011; 7:96–104. This is the most updated and comprehensive review on the role of ANKH in the pathogenesis of CPPD. PubMedCrossRefGoogle Scholar
  17. 17.
    Tsui FWL, Las Heras F, Inman RD, et al. Functional roles of ANKH/Ank: insights from CPPDD-associated ANKH mutations and the ank/ank mouse. JCRMM. 2010;Mar.Google Scholar
  18. 18.
    Collins MT, Boehm M. It ANKH necessarily so. J Clin Endocrinol Metab. 2011;95:72–4.CrossRefGoogle Scholar
  19. 19.
    •• Wang J, Tsui HW, Beier F, et al. The CPPDD-associated ANKH M48T mutation interrupts the interaction of ANKH with the sodium/phosphate cotransporter PiT-1. J Rheumatol. 2009; 36:1265–72. This is the first report of a protein, PiT-1, that normally interacts with ANKH, but the mutant ANKH M48T protein could no longer interact with PiT-1. This result suggested a coordinated interrelationship between two key proteins involved in Pi and PPi metabolism. Whether the disruption of the ANKH–PiT-1 interaction is sufficient for the development of CPPD in patients with this ANKH mutation is not known. PubMedCrossRefGoogle Scholar
  20. 20.
    • Morava E, Kühnisch J, Drijvers JM, et al. Autosomal recessive mental retardation, deafness, ankylosis and mild hypophophatemia associated with a novel ANKH mutation in a consanguineous family. J Clin Endocrinol Metab. 2011; 96:E189-98. This is the first report of a recessive ANKH mutation (L244S) in humans and the first report of mental retardation associated with an ANKH mutation. PubMedCrossRefGoogle Scholar
  21. 21.
    Yamamoto T, Kurihara N, Yamaoka K, et al. Bone marrow-derived osteoclast-like cells from a patient with craniometaphyseal dysplasia lack expression of osteoclast-reactive vacuolar proton pump. J Clin Invest. 1993;91:362–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen IP, Wang CJ, Strecker S, et al. Introduction of a Phe377del mutation in ANK creates a mouse model for craniometaphyseal dysplasia. J Bone Miner Res. 2009;24:1206–15.PubMedCrossRefGoogle Scholar
  23. 23.
    • Zajac A, Baek S-H, Salhab I, et al. Novel ANKH mutation in a patient with sporadic caraniometaphyseal dysplasia. Am J Med Genet. 2010; Part A 152A:770–6. The complex ANKH exon 7 mutations resulted in the retention of the mutant ANKH protein in the cytoplasm and were unable to be expressed on the cell surface, indicating that this represents a loss-of-function mutation. Google Scholar
  24. 24.
    Cheng P-T, Pritzker KPH. Pyrophosphate, phosphate ion interaction: effects on calcium pyrophosphate and calcium hydroxyapatite crystal formation in aqueous solutions. J Rheumatol. 1983;10:769–77.PubMedGoogle Scholar
  25. 25.
    Thouverey C, Bechkoff G, Pikula S, et al. Inorganic pyrophosphate as a regulator of hydroxyapatite or calcium pyrophosphate dihydrate mineral deposition by matrix vesicles. Osteoarthritis Cartilage. 2009;17:64–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Costello JC, Rosenthal AK, Kurup IV, et al. Parallel regulation of extracellular ATP and inorganic pyrophosphate: roles of growth factors, transduction modulators and ANK. Connect Tissue Res. 2011;52:139–46.PubMedCrossRefGoogle Scholar
  27. 27.
    Pritzker KPH, Chateauvert JMD, Grynpas MD. Osteoarthritic cartilage contains increased calcium, magnesium and phosphorus. J Rheumatol. 1987;14:806–10.PubMedGoogle Scholar
  28. 28.
    So PP, Tsui FW, Vieth R, et al. Inhibition of alkaline phosphatase by cysteine: implications for calcium pyrophosphate dihydrate crystal deposition disease. J Rheumatol. 2007;34:1313–22.PubMedGoogle Scholar
  29. 29.
    Wang J, Tsui HW, Beier F, et al. The ANKH ΔE490 mutation in calcium pyrophosphate dihydrate crystal deposition disease (CPPDD) affects tissue non-specific alkaline phosphatase (TNAP) activities. Open Rheumatol J. 2008;2:25–32.Google Scholar
  30. 30.
    Shinozaki T, Pritzker KPH. Regulation of alkaline phosphatase: implications for calcium pyrophosphate dehydrate crystal dissolution and other alkaline phosphatase functions. J Rheumatol. 1996;23:677–83.PubMedGoogle Scholar
  31. 31.
    Zaka R, Stokes D, Dion AS, et al. P5L mutation in Ank results in an increase in extracellular inorganic pyrophosphate during proliferation and nonmineralizing hypertrophy in stably transduced ATDC5 cells. Arthritis Res Ther. 2006;8:R164.PubMedCrossRefGoogle Scholar
  32. 32.
    Zaka R, Dion A, Kusnierz A, et al. Oxygen tension regulates the expression of ANK (Progressive Ankylosis) in an HIF-1-dependent manner in growth plate chondrocytes. J Bone Miner Res. 2009;24:1869–78.PubMedCrossRefGoogle Scholar
  33. 33.
    Kim HJ, Delaney JD, Kirsch T. The role of pyrophosphate/phosphate homeostasis in terminal differentiation and apoptosis of growth plate chondrocytes. Bone. 2010;47:657–65.PubMedCrossRefGoogle Scholar
  34. 34.
    Foster BL, Hociti Jr FH, Swanson EC, et al. Regulation of cementoblast gene expression by inorganic phosphate in vitro. Calcif Tissue Int. 2006;78:103–12.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang Y, Brown MA, Peach C, et al. Investigation of the role of ENPP1 and TNAP genes in chondrocalcinosis. Rheumatology. 2006;13:1–4.Google Scholar
  36. 36.
    Guo Y, Hsu DKW, Feng S-L, et al. Polypeptide growth factors and phorbol ester induce progressive ankylosis (Ank) gene expression in murine and human fibroblasts. C Cell Biochem. 2002;84:27–38.CrossRefGoogle Scholar
  37. 37.
    Palmer G, Guicheux J, Bonhour JP, et al. Transforming growth factor beta stimulates inorganic phosphate transport and expression of the type III phosphate transporter Glvr-1 in chondrogenic ATDC5 cells. Endocrinology. 2000;141:2236–43.PubMedCrossRefGoogle Scholar
  38. 38.
    Ding J, Ghali O, Lencel P, et al. TNF-alpha and IL1-beta inhibits RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells. Life Sci. 2009;84:499–504.PubMedCrossRefGoogle Scholar
  39. 39.
    Hirose J, Ryan LM, Masuda I. Up-regulated expression of cartilage intermediate-layer protein and ANK in articular hyaline cartilage from patients with calcium pyrophosphate dehydrate crystal deposition disease. Arthritis Rheum. 2002;46: 3218–29.PubMedCrossRefGoogle Scholar
  40. 40.
    Gaucher A, Faure G, Netter P, et al. Hereditary diffuse articular chondrocalcinosis. Dominant manifestation without close linkage with the HLA system in a large pedigree. Scand J Rheumatol. 1977;6:217–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Gurley KA, Reimer RJ, Kingsley DM. Biochemical and genetic analysis of ANK in arthritis and bone disease. Am J Hum Genet. 2006;79:1017–29.PubMedCrossRefGoogle Scholar
  42. 42.
    Murshed M, Harmey D, Millan JL, et al. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev. 2005;19:1093–104.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Toronto Western HospitalTorontoCanada

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