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Pathogenesis of Chondrocalcinosis and Pseudogout. Metabolism of Inorganic Pyrophosphate and Production of Calcium Pyrophosphate Dihydrate Crystals

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Pathogenesis of Chondrocalcinosis and Pseudogout. Metabolism of Inorganic Pyrophosphate and Production of Calcium Pyrophosphate Dihydrate Crystals Ann Rheum Dis: first published as 10.1136/ard.42.Suppl_1.27 on 1 January 1983. Downloaded from Ann Rheum Dis (1983), 42, Supplement p 27 Pathogenesis of chondrocalcinosis and pseudogout. Metabolism of inorganic pyrophosphate and production of calcium pyrophosphate dihydrate crystals A. CASWELL, D. F. GUILLAND-CUMMING, P. R. HEARN, M. K. B. McGUIRE, R. G. G. RUSSELL From Department of Human Metabolism and Clinical Biochemistry, University ofSheffield Medical School, Beech Hill Road, Sheffield S10 2RX. Introduction General considerations pseudogout." '" Here there is an enzyme defect, a deficiency of alkaline Calcium pyrophosphate dihydrate Table 1 summarises the factors to be phosphatase with resultant rise of (CPPD) is one of several types of considered in relation to the inorganic pyrophosphate (PP,) in body crystal that may be deposited in the deposition of CPPD crystals and the fluids. Hypophosphatasia is the best body. The term chondrocalcinosis is association of chondrocalcinosis with example of how an abnormality in used to describe the radiographic endocrine and metabolic diseases. The pyrophosphate metabolism may by copyright. appearance of calcified deposits, reasons for these clinical associations contribute to the production of notably in the articular cartilage and are not always clear but they indicate chondrocalcinosis, but raises the menisci of the knees but also in other that a variety of metabolic disturbances intriguing question of why CPPD joints.' Not all calcified deposits within may lead to deposition of crystals appear in the typical sites in joints are due to calcium pyrophosphate crystals. cartilage, even though PP, pyrophosphate; however, occasional CPPD deposition is also more concentrations are raised deposition of apatite,2 calcium common in the presence of other joint systemically. dihydrogen phosphate,' and oxalate disease, including osteoarthropathy,5 It is apparent that chondrocalcinosis also occurs. neuropathic (Charcot) joint disease,7 must be considered a multifactoral McCarty was the first to identify and gout.5 In such cases the destructive problem in which several metabolic CPPD crystals in synovial fluids taken changes that occur may induce and physiochemical factors probably from patients thought to have gouty alterations of pyrophosphate interact to produce CPPD crystals. http://ard.bmj.com/ arthritis,"5 He found the crystals to be metabolism within the joint leading to Before considering the mechanisms of the calcium pyrophosphate dihydrate increased crystal formation. crystallisation involved in production salt in its triclinic form. Shedding The increased incidence of CPPD of CPPD crystals, we will first review crystals into the synovial space deposition with aging may also be current knowledge of pyrophosphate produces acute or chronic attacks of related to the changes that occur in metabolism. pseudogout.6 cartilage with age. Certain considerations apply to all A familial form of chondrocalcinosis Intracellular metabolism of inorganic on September 27, 2021 by guest. Protected forms of crystal deposition, in was described by Zitnan and Sit'aj in pyrophosphate particular the factors determining 1958," although at that time it was whether or not crystallisation occurs. not known that CPPD was the calcium This largely concerns the activity salt responsible. Subsequently other GENERAL CONDITIONS products of the ions involved, although familial forms have been Inorganic pyrophosphate (PP,) is the presence of nucleating agents or described.'0"'- The existence of these produced at one or more steps in a inhibitory agents, or both, must be inherited forms allow a comparison wide variety of biochemical pathways considered. Solubilisation processes with classic gout where specific that lead to the synthesis of most of the may also be important. enzyme defects have occasionally been major cell constituents. Hence The purpose of this presentation is identified--for example, in the generation of PPi occurs during the twofold: (a) to review current Lesch-Nyhan syndrome.'3 The biosynthesis of proteins, lipids, knowledge of the metabolism of underlying metabolic defect in the phospholipids, nucleotides, and inorganic pyrophrosphate and (b) to familial forms of chondrocalcinosis is nucleic acids, urea, steroids, structural describe some of the mechanisms that still not determined but may entail polysaccharides, and glycogen. may be involved in the production of enzyme abnormalities. Breakdown of pyrophosphate is CPDD crystals, both in vitro and in Hypophosphatasia is an inherited brought about by a hydrolysis reaction vivo. disorder associated with catalysed by inorganic Ann Rheum Dis: first published as 10.1136/ard.42.Suppl_1.27 on 1 January 1983. Downloaded from Suppl p 28 Annals ofthe Rheumatic Diseases Table 1 Conditions associated with deposition ofcrystals ofcakium pyrophosphate dihy- concentration of intracellular PPi drate (CPPD) in joints (chondrocalcinosis). Note the large number ofpossible underlying would be under metabolic control and mechanisms. could respond to changes in the rates of either its synthesis or degradation. Possible mechanisms involved Furthermore, if the intracellular Inherited forms: concentration of PP1 does change in Described from Possible abnormality in inorganic pyrophosphate response to different metabolic Czechoslovakia, Chile, Netherlands, (PP,) metabolism-for example, over- conditions, it becomes possible for this Sweden, France, USA production of PP, or decreased degradation of ion itself to be involved in the PP1 (possible changes in pyrophosphatases). regulation of metabolism. Reduced inhibitors of crystallisation. General associations: Aging Disturbed PP1 metabolism. IS THE PPi HYDROLYSIS Physical damage to chondrocytes. REACTION IN EQUILIBRIUM? Release of nucleating agents or decreased Attempts to determine the inhibitory activity (perhaps via action of released equilibrium constant and free energy proteases to destroy inhibitors). Increased change for hydrolysis of PP, under cartilage permeation by Ca"+ and PP1. stimulated physiological conditions Other joint disease: have produced variable results.20 22 Osteoarthritis Epitaxy on apatite crystals. Neuropathic joint disease pH may be lowered during inflammation which However, the reported tissue (Charcot joints) promotes crystal transformations to more concentrations of PPi appear to exceed Destructive arthropathy insoluble forms. those calculated from values found for Ochronosis the equilibrium constant,'8 19 23 Rheumatoid arthritis supporting the view that the hydrolysis Urate gout Epitaxy on urate crystals reaction is not in equilibrium. Using Metabolic disorders: freeze-clamped rat tissues we have Hyperparathyroidism Raised extracellular Ca, and/or raised PP1 due to increased adenylate cyclase activity. recently demonstrated that the total by copyright. Hypothyroidism Metabolic changes in cartilage PP, content of skeletal muscle (50 Hypophosphatasia Raised PP1 due to alkaline phosphatase deficiency nmol/g) is substantially higher than Haemochromatosis Fe as nucleating agent or that found in liver, kidney, heart, and pyrophosphatase inhibitor lung tissues (20 nmol/g) (unpublished Long-term steroid therapy Secondary hyperparathyroidism observations). Similarly, with isolated Possible associations: human cells, it has been observed that Hypertension fibroblasts and synovial cells contain Renal insufficiency High PP, in chronic renal failure; acidosis promotes than and bone crystal transformation to insoluble forms less PP1 chondrocytes Acromegaly Metabolic alterations in cartilage cells. Furthermore, the higher PP1 Paget's disease Age related content of chondrocytes relative to Diabetes mellitus fibroblasts appears to be correlated http://ard.bmj.com/ Wilson's disease Copper as crystal nucleating agent or with differences in the rate of pyrophosphatase inhibitor proteoglycan synthesis in these two cell types.24.26 Several studies have shown that both the total PP1 content and the calculated cytoplasmic free PP1 pyrophosphatases, in which 2 mol of hydrolysis reaction for PP1 is at content of freeze-clamped rat liver orthophosphate (Pi) are produced per equilibrium in vivo. An alternative may change quite considerably after mol of PP1 cleaved. Such enzymes possibility may be that inorganic various short term or long term on September 27, 2021 by guest. Protected include glucose- 6-phosphatase and pyrophosphatase is a nonequilibrium metabolic manipulations-for alkaline phosphatase, as well as more enzyme and that its activity is the example, after administration of specific inorganic pyrophosphatases. limiting factor in the removal of PP1. acetate or butyrate or after 48 hours' The metabolic importance of PP1 Additional determinants of the starvation."9 21 23 Such studies have has yet to be defined. The assumption intracellular steady state led to the suggestion that hepatic that intracellular concentrations of PP1 concentration of PP1 may be the glucose uptake and phosphorylation are very low led Kornberg and others'6 intracellular concentration of Pi, both are regulated predominantly by 1 to point out that the removal of PP, as a result of the effect of Pi on the changes in the concentration of free provides a means of driving equilibrium reaction, and because it is PPi in cytoplasm,2' thereby indicating pyrophosphorylase reactions in the a competitive inhibitor of a role for PP1 in metabolic regulation. direction of synthesis, essentially pyrophosphatases. If the An increase in the intracellular
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