Inorganic pyrophosphate (PPI) in pathologic calcification of articular cartilage.
Physiologic levels of extracellular PPi, which suppresses hydroxyapatite crystal growth, must be maintained by articular chondrocytes and resident cells in many othee tissues in order to prevent pathologic calcification. However, extracellular PPi rises in articular cartilage in direct association with aging. Matrix supersaturation with PPi stimulates chondrocalcinosis manifesting as calcium pyrophosphate dihydrate (CPPD) crystal deposition. Extracellular PPi levels are normally held in check by balances in PPi generation by nucleotide pyrophosphatase phosphodiesterase (NPP/NTPPPH) activity relative to PPi degradation by pyrophosphatases, by balance effects of cytokines and growth factors, and by transport of PPi from the cell interior involving the multiple-pass transmembrane protein ANK. But these mechanisms become dysrgulated in aging and osteoarthritic (OA) cartilage and extracellular PPi excess supervenes, mediated in large part by upregulated NPP1 and ANK expression in articular cartilage. Conversely, NPP1 and ANK deficiency states were recently linked to phenotypically similar forms of spontaneous soft tissue calcification with hydroxyapatite (HA). Here, we focus on recent advances in understanding of PPi metabolism and NPP1 and ANK function pertinent to the pathogenesis of pathologi matrix calcification in articular cartilage.
Johnson
Kristen
K
Rheumatology Section, San Diego Veterans Affairs Medical Center, University of California School of Medicine, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Terkeltaub
Robert
R
D000818:Animals; D002114:Calcinosis; D002356:Cartilage / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism; D003460:Crystallization; D006801:Humans; D009154:Mutation; D053495:Osteopontin; D010641:Phenotype; D010710:Phosphates / Q000737:chemistry; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism
D010710:Phosphates; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D053495:Osteopontin; D010749:Phosphoprotein Phosphatases; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; C405782:nucleotide pyrophosphatase - phosphodiesterase I