pyrophosphate and Ankylosis

Pathologic soft tissue calcification can occur in both genetic and acquired clinical conditions, causing significant morbidity and mortality. Although the pathomechanisms of pathologic calcification are poorly understood, major progress has been made in recent years in defining the underlying genetic defects in Mendelian disorders of ectopic calcification. This review presents an overview of the pathophysiology of five monogenic disorders of pathologic calcification: pseudoxanthoma elasticum, generalized arterial calcification of infancy, arterial calcification due to deficiency of CD73, ankylosis, and progeria. These hereditary disorders, caused by mutations in genes encoding ATP binding cassette subfamily C member 6, ectonucleotide pyrophosphatase/phosphodiesterase 1, CD73, progressive ankylosis protein, and lamin A/C proteins, respectively, are inorganic pyrophosphate (PPi) deficiency syndromes with reduced circulating levels of PPi, the principal physiologic inhibitor of calcium hydroxyapatite deposition in soft connective tissues. In addition to genetic diseases, PPi deficiency has been encountered in acquired clinical conditions accompanied by pathologic calcification. Because specific and effective treatments are lacking for pathologic calcification, the unifying finding of PPi deficiency suggests that PPi-targeted therapies may be beneficial to counteract pathologic soft tissue calcification in both genetic and acquired diseases.

Topics: Ankylosis; Calcinosis; Choristoma; Diphosphates; Humans; Pseudoxanthoma Elasticum; Syndrome; Vascular Calcification

Pyrophosphate inhibits mineralization, and tissue non-specific alkaline phosphatase (TNSALP) increases phosphate concentration by cleaving pyrophosphate, which is important for the regulation of mineralization in bone. Moreover, PC-1 (plasma cell membrane glycoprotein-1) on matrix vesicle and osteoblast plasma membrane, as well as ANK (ankylosis) on osteoblast plasma membrane induce extracellular pyrophosphate. The pyrophosphate production by PC-1 and ANK and TNSALP, as well as some mineralization-inhibiting factors, (for example osteopontin) induced by these molecules, is considered to maintain the normal process of mineralization. The abnormality of these molecules causes various mineralization disorders.

Topics: Alkaline Phosphatase; Animals; Ankylosis; Calcification, Physiologic; Diphosphates; Mice; Phosphoric Diester Hydrolases; Pyrophosphatases

Familial calcium pyrophosphate dihydrate deposition (CPPD) disease is a chronic condition in which CPPD microcrystals deposit in the joint fluid, cartilage, and periarticular tissues. Two forms of familial CPPD disease have been identified: CCAL1 and CCAL2. The CCAL1 locus is located on the long arm of chromosome 8 and is associated with CPPD and severe osteoarthritis. The CCAL2 locus has been mapped to the short arm of chromosome 5 and identified in families from the Alsace region of France and the United Kingdom. The ANKH protein is involved in pyrophosphate metabolism and, more specifically, in pyrophosphate transport from the intracellular to the extracellular compartment. Numerous ANKH gene mutations cause familial CCAL2; they enhance ANKH protein activity, thereby elevating extracellular pyrophosphate levels and promoting the formation of pyrophosphate crystals, which produce the manifestations of the disease. Recent studies show that growth factors and cytokines can modify the expression of the normal ANKH protein. These results suggest a role for ANKH in sporadic CPPD disease and in CPPD associated with degenerative disease.

Topics: Animals; Ankylosis; Chondrocalcinosis; Diphosphates; Homozygote; Humans; Membrane Proteins; Mice; Mutation; Phosphate Transport Proteins