Pathogenesis and etiology of calcium pyrophosphate crystal deposition (CPPD) disease
- Michael A Becker, MD
Michael A Becker, MD
- Section Editor — Crystal Diseases
- Professor Emeritus of Medicine
- University of Chicago Pritzker School of Medicine
- Lawrence M Ryan, MD
Lawrence M Ryan, MD
- Will and Cava Ross Professor of Medicine Emeritus
- Medical College of Wisconsin
Precipitation of crystals of calcium pyrophosphate dihydrate (CPP) in connective tissues may be asymptomatic or may be associated with several clinical syndromes associated with acute and chronic arthritis. These disorders comprise the spectrum of calcium pyrophosphate crystal deposition (CPPD) disease .
The pathogenesis and etiology of CPPD disease will be reviewed here. The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease" and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease".)
Calcium pyrophosphate dihydrate (CPP) was formerly abbreviated and commonly referred to as “CPPD” because the dihydrate is necessary for crystallization; but the abbreviation “CPPD” is now reserved for “CPP deposition.” Alternative names representing specific clinical or radiographic features of CPPD disease, including pseudogout, chondrocalcinosis, and pyrophosphate arthropathy, have retained some popularity, but each has limitations:
●Pseudogout/acute CPP crystal arthritis – Pseudogout is a term that has historically been used in two contexts: first, to differentiate the overall concept of CPPD disease from that of monosodium urate crystal deposition disease (gout or urate gout); and second, to describe acute attacks of CPP crystal-induced arthritis clinically resembling those commonly encountered in urate gout. The term “acute CPP crystal arthritis” is now preferred in place of “pseudogout” to describe the latter instance .
●Chondrocalcinosis – Chondrocalcinosis refers to radiographic calcification in hyaline and/or fibrocartilage. It is commonly present in patients with CPPD, but is neither absolutely specific for CPPD nor universal among affected patients.
- Rosenthal AK. Pseudogout: Presentation, natural history, and associated conditions. In: Crystal-Induced Arthropathies: Gout, Pseudogout, and Apatite-Associated Syndromes, Wortmann RL, Schumacher HR Jr, Becker MA, Ryan LM (Eds), Taylor & Francis Group, New York 2006. p.99.
- 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.
- Masuda I, Ishikawa K, Usuku G. A histologic and immunohistochemical study of calcium pyrophosphate dihydrate crystal deposition disease. Clin Orthop Relat Res 1991; :272.
- Reginato AJ, Schumacher HR, Martinez VA. The articular cartilage in familial chondrocalcinosis. Light and electron microscopic study. Arthritis Rheum 1974; 17:977.
- Ryan LM, Rachow JW, McCarty DJ. Synovial fluid ATP: a potential substrate for the production of inorganic pyrophosphate. J Rheumatol 1991; 18:716.
- Rachow JW, Ryan LM. Adenosine triphosphate pyrophosphohydrolase and neutral inorganic pyrophosphatase in pathologic joint fluids. Elevated pyrophosphohydrolase in calcium pyrophosphate dihydrate crystal deposition disease. Arthritis Rheum 1985; 28:1283.
- Tenenbaum J, Muniz O, Schumacher HR, et al. Comparison of phosphohydrolase activities from articular cartilage in calcium pyrophosphate deposition disease and primary osteoarthritis. Arthritis Rheum 1981; 24:492.
- Ryan LM, Wortmann RL, Karas B, McCarty DJ Jr. Cartilage nucleoside triphosphate (NTP) pyrophosphohydrolase. I. Identification as an ecto-enzyme. Arthritis Rheum 1984; 27:404.
- Okawa A, Nakamura I, Goto S, et al. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet 1998; 19:271.
- Siegel SA, Hummel CF, Carty RP. The role of nucleoside triphosphate pyrophosphohydrolase in in vitro nucleoside triphosphate-dependent matrix vesicle calcification. J Biol Chem 1983; 258:8601.
- Derfus BA, Rachow JW, Mandel NS, et al. Articular cartilage vesicles generate calcium pyrophosphate dihydrate-like crystals in vitro. Arthritis Rheum 1992; 35:231.
- Johnson K, Pritzker K, Goding J, Terkeltaub R. The nucleoside triphosphate pyrophosphohydrolase isozyme PC-1 directly promotes cartilage calcification through chondrocyte apoptosis and increased calcium precipitation by mineralizing vesicles. J Rheumatol 2001; 28:2681.
- Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank gene in control of tissue calcification and arthritis. Science 2000; 289:265.
- Rosenthal AK, Gohr CM, Mitton-Fitzgerald E, et al. The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes. Arthritis Res Ther 2013; 15:R154.
- Xu H, Zhang X, Wang H, et al. Continuous cyclic mechanical tension increases ank expression in endplate chondrocytes through the TGF-β1 and p38 pathway. Eur J Histochem 2013; 57:e28.
- Skubutyte R, Markova D, Freeman TA, et al. Hypoxia-inducible factor regulation of ANK expression in nucleus pulposus cells: possible implications in controlling dystrophic mineralization in the intervertebral disc. Arthritis Rheum 2010; 62:2707.
- 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.
- Pendleton A, Johnson MD, Hughes A, et al. Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet 2002; 71:933.
- Hughes AE, McGibbon D, Woodward E, et al. Localisation of a gene for chondrocalcinosis to chromosome 5p. Hum Mol Genet 1995; 4:1225.
- Andrew LJ, Brancolini V, de la Pena LS, et al. Refinement of the chromosome 5p locus for familial calcium pyrophosphate dihydrate deposition disease. Am J Hum Genet 1999; 64:136.
- Zhang Y, Johnson K, Russell RG, 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.
- Abhishek A, Doherty S, Maciewicz R, et al. The association between ANKH promoter polymorphism and chondrocalcinosis is independent of age and osteoarthritis: results of a case-control study. Arthritis Res Ther 2014; 16:R25.
- Uzuki M, Sawai T, Ryan LM, et al. Upregulation of ANK protein expression in joint tissue in calcium pyrophosphate dihydrate crystal deposition disease. J Rheumatol 2014; 41:65.
- Dalbeth N, Haskard DO. Pathophysiology of crystal-induced arthritis. In: Crystal-Induced Arthropathies: Gout, Pseudogout, and Apatite-Associated Syndromes, Wortmann RL, Schumacher HR Jr, Becker MA, Ryan LM (Eds), Taylor & Francis Group, New York 2006. p.239.
- Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440:237.
- Cheung HS, Story MT, McCarty DJ. Mitogenic effects of hydroxyapatite and calcium pyrophosphate dihydrate crystals on cultured mammalian cells. Arthritis Rheum 1984; 27:668.
- Wilkins E, Dieppe P, Maddison P, Evison G. Osteoarthritis and articular chondrocalcinosis in the elderly. Ann Rheum Dis 1983; 42:280.
- Nalbant S, Martinez JA, Kitumnuaypong T, et al. Synovial fluid features and their relations to osteoarthritis severity: new findings from sequential studies. Osteoarthritis Cartilage 2003; 11:50.
- Ryu K, Iriuchishima T, Oshida M, et al. The prevalence of and factors related to calcium pyrophosphate dihydrate crystal deposition in the knee joint. Osteoarthritis Cartilage 2014; 22:975.
- Burt HM, Jackson JK, Rowell J. Calcium pyrophosphate and monosodium urate crystal interactions with neutrophils: effect of crystal size and lipoprotein binding to crystals. J Rheumatol 1989; 16:809.
- Kumagai Y, Watanabe W, Kobayashi A, et al. Inhibitory effect of low density lipoprotein on the inflammation-inducing activity of calcium pyrophosphate dihydrate crystals. J Rheumatol 2001; 28:2674.
- Jones AC, Chuck AJ, Arie EA, et al. Diseases associated with calcium pyrophosphate deposition disease. Semin Arthritis Rheum 1992; 22:188.
- Doherty M, Watt I, Dieppe PA. Localised chondrocalcinosis in post-meniscectomy knees. Lancet 1982; 1:1207.
- Lindén B, Nilsson BE. Chondrocalcinosis following osteochondritis dissecans in the femur condyles. Clin Orthop Relat Res 1978; :223.
- Punzi L, Calò L, Schiavon F, et al. Chondrocalcinosis is a feature of Gitelman's variant of Bartter's syndrome. A new look at the hypomagnesemia associated with calcium pyrophosphate dihydrate crystal deposition disease. Rev Rhum Engl Ed 1998; 65:571.
- Cobeta-Garcia JC, Gascón A, Iglesias E, Estopiñán V. Chondrocalcinosis and Gitelman's syndrome. A new association? Ann Rheum Dis 1998; 57:748.
- Luzar MJ, Altawil B. Pseudogout following intraarticular injection of sodium hyaluronate. Arthritis Rheum 1998; 41:939.
- Disla E, Infante R, Fahmy A, et al. Recurrent acute calcium pyrophosphate dihydrate arthritis following intraarticular hyaluronate injection. Arthritis Rheum 1999; 42:1302.
- Pullman-Mooar S, Mooar P, Sieck M, et al. Are there distinctive inflammatory flares after hylan g-f 20 intraarticular injections? J Rheumatol 2002; 29:2611.
- Geelhoed GW, Kelly TR. Pseudogout as a clue and complication in primary hyperparathyroidism. Surgery 1989; 106:1036.
- Malnick SD, Ariel-Ronen S, Evron E, Sthoeger ZM. Acute pseudogout as a complication of pamidronate. Ann Pharmacother 1997; 31:499.