Date: 24 Dec 2011
Genetics and Mechanisms of Crystal Deposition in Calcium Pyrophosphate Deposition Disease
- Florence W. L. Tsui
- … show all 1 hide
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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.
•• 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. PubMedCrossRef
•• 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. PubMedCrossRef
• 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. PubMed
Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dehydrate crystal deposition disease. Rheumatol. 2009;48:711–5.CrossRef
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.PubMed
Pendleton A, Johnson MD, Hughes A, et al. Mutations in ANKH caused chondrocalcinosis. Am J Hum Genet. 2001;71:933–40.CrossRef
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.PubMedCrossRef
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.PubMed
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.
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.
Collins MT, Boehm M. It ANKH necessarily so. J Clin Endocrinol Metab. 2011;95:72–4.CrossRef
•• 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. PubMedCrossRef
• 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. PubMedCrossRef
• 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.
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.PubMed
Pritzker KPH, Chateauvert JMD, Grynpas MD. Osteoarthritic cartilage contains increased calcium, magnesium and phosphorus. J Rheumatol. 1987;14:806–10.PubMed
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.PubMed
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.
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.PubMed
Zhang Y, Brown MA, Peach C, et al. Investigation of the role of ENPP1 and TNAP genes in chondrocalcinosis. Rheumatology. 2006;13:1–4.
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.CrossRef
- Genetics and Mechanisms of Crystal Deposition in Calcium Pyrophosphate Deposition Disease
Current Rheumatology Reports
Volume 14, Issue 2 , pp 155-160
- Cover Date
- Print ISSN
- Online ISSN
- Current Science Inc.
- Additional Links
- Calcium pyrophosphate deposition (CPPD)
- Chondrocalcinosis (CC)
- Human homologue of progressive ankylosis (ANKH)
- Familial disease
- Animal models
- Tissue nonspecific alkaline phosphatase (TNAP)
- Sodium/phosphate co-transporter PiT-1
- Crystal deposition
- Crystal arthritis
- Industry Sectors
- Author Affiliations
- 1. Toronto Western Hospital, Mc14-419, 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada