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Hot Topic Review |
1 Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK 2 Institute of Human Genetics, International Centre for Life, Central Parkway, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 3BZ, UK
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(Received 21 September 2007;
accepted after revision 2 October 2007; first published online 2 October 2007)
Corresponding author N. L. Simmons: Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK. Email: n.l.simmons{at}ncl.ac.uk
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Introduction |
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It has been known for many years that pyrophosphate (PPi) is a potent inhibitor of hydroxyapatite crystallization (Fleisch & Bisaz, 1962; Russell, 1976). Pyrophosphate inhibits crystallization by binding to the surface of basic calcium phosphate crystals (this includes hydroxyapatite) and blocking further crystal growth (Jung et al. 1973). Pyrophosphate is involved in many aspects of cellular physiology, with roles in intracellular calcium trafficking and modification of enzyme function, as well as being a metabolic byproduct, for example in the hydrolysis of adenosine triphosphate (ATP) by adenylate cyclase (Rachow & Ryan, 1988). In vivo PPi turnover studies suggest that most PPi metabolism is intracellular (Jung et al. 1970); however, recent work emphasizes its extracellular role in inhibition of bone mineralization (Harmey et al. 2004). Excess extracellular PPi inhibits mineralization, whereas a higher inorganic phosphate (Pi):PPi ratio leads to increased mineralization. In this review, the participation of extracellular PPi in the prevention of hydroxyapatite formation within the kidney is advanced as a key physiological mechanism in the prevention of calcium renal stone formation.
Pyrophosphate in bone and joint mineralization
An integrated model of bone mineralization is now apparent, in which local PPi antagonizes the promotion of hydroxyapatite formation by inorganic phosphate (Harmey et al. 2004). Three main proteins regulate this process, the control of which is summarized in Fig. 1. Extracellular PPi is generated from nucleoside triphosphates by the nucleotide pyrophosphatase phosphodiesterase (NPP) ectoenzyme. enpp1 (NPP1) knock-out mice demonstrate hypermineralization, particularly of articular cartilage, which results in intervertebral ankylosis (fusion) and peripheral joint hyperostosis (Harmey et al. 2004). Additionally, the progressive ankylosis (ank) gene (ANKH in humans) encodes a transmembrane transport protein which mediates PPi export from the cytoplasm to the extracellular space. The ANK protein has now been conclusively linked with tissue calcification in both mice and humans (Ho et al. 2000). Mutant mice in which the ank locus is mutated so that ANK is non-functional have a similar phenotype to enpp1 knock-out mice, as do ank–/– knock-out animals (Gurley et al. 2006a); the decreased extracellular PPi results in basic calcium phosphate deposition, so leading to progressive ankylosis of joints. Inactivating mutations in the human ANKH gene result in a specific hypermineralization disorder known as craniometaphyseal dysplasia (OMIM 123000 [OMIM] ), and have been shown to suppress 32PPi influx when expressed in Xenopus oocytes (Gurley et al. 2006b). Hence, deficiencies in both NPP1 and ANK can disturb the balance between inorganic phosphate and PPi extracellularly, causing increased hydroxyapatite deposition. Similarly, a familial PPi deposition disease (calcium pyrophosphate dihydrate deposition disease, CCAL2; OMIM 118600 [OMIM] ) may result from gain-of-function mutations in ANKH, although direct evidence for enhanced ANKH protein expression or PPi transport is lacking (Pendleton et al. 2002; Gurley et al. 2006b). The evidence from both craniometaphyseal dysplasia and CCAL2 reinforces a central role for ANKH and PPi in the control of bone mineralization (Fig. 1).
A third gene, akp2, encodes tissue non-specific alkaline phosphatase (TNAP, also known as TNSALP and ALPL), which hydrolyses PPi, other phosphate substrates and the phosphorylated glycoprotein osteopontin, to release inorganic phosphate. Activity of TNAP therefore promotes appropriate calcification by lowering PPi levels and increasing inorganic phosphate (Fig. 2). Akp2 knock-out mice exhibit decreased bone mineralization resulting from the decrease in phosphatase activity (Harmey et al. 2004). Mutations in the gene encoding human TNAP similarly cause hypophosphatasia, a syndrome that includes osteomalacia and increased risk of bone fractures, and which is characterized by increased urinary PPi excretion (Whyte, 1994). In addition, extracellular PPi controls the expression of osteopontin, the phosphorylated protein inhibitor of mineralization (Harmey et al. 2004). Osteoblasts incubated in high PPi concentrations display increased osteopontin production via the Erk1/2 and p38 mitogen activated protein kinase (MAPK) signalling pathways (Addison et al. 2007). High PPi also inhibits TNAP activity (Addison et al. 2007). Both Enpp1 and ank knock-out animals show decreased osteopontin levels (Harmey et al. 2004). Hence, extracellular PPi can further inhibit mineralization by upregulating osteopontin production.
Molecular biology of ANKH
While NPP1 localizes to vesicles in the extracellular matrix surrounding chondrocytes and osteoblasts (Harmey et al. 2004), the component of extracellular PPi which is derived from intracellular metabolism originates mainly via the specific membrane ANK transporter (Terkeltaub, 2001). The ANKH gene on chromosome 5p encodes a 492-amino acid, 54.3 kDa (Ho et al. 2000), 10 or 12 transmembrane segment protein (Nurnberg et al. 2001) that is expressed in several tissues, including articular cartilage. There is significant conservation of the ANK protein across mammalian species, and the human homologue ANKH is virtually identical (98%) to that in the mouse. Among vertebrates, zebrafish ANK shows a striking 82% amino acid identity with human ANKH (Nurnberg et al. 2001).
Ho et al. (2000) were the first to show that ANK has a role in PPi transport. Fibroblasts cultured from mutant ank/ank mice showed increased intracellular PPi but decreased extracellular PPi levels compared with control fibroblasts from wild-type mice. Transfection of ank/ank fibroblasts to produce normal ANK protein rescued these changes, consistent with ANK-mediated PPi transport from cell to medium. This transport could be blocked by probenecid (2.5 mM), a non-specific anion transport inhibitor. More recently, expression of ANK in Xenopus oocytes has confirmed 32PPi influx into the oocytes, which showed saturation by external PPi with an apparent Km of 
2 µM (Gurley et al. 2006b). The ANK protein is therefore unlikely to be an anion channel, but little else is known about ANK function (whether facilitated transporter, symporter or antiporter) and its specificity with respect to anions such as phosphate or even ATP (suggested by Ryan, 2001).
Pyrophosphate as a calcification inhibitor in the kidney
Fleisch & Bisaz (1962) first demonstrated PPi as an inhibitor of calcification routinely present in human urine, at concentrations of 10 µM (range 8–16 µM; March et al. 2001). Pyrophosphate added to urine appears to be relatively stable, with complete recovery from an anion exchange resin being possible (March et al. 2001). Twenty-four hour urinary outputs of PPi are positively correlated with urine volume (Roberts et al. 1992), but PPi is elevated in the most concentrated (low volume) samples (Roberts et al. 1992). Calcium stone formers appear, on balance, to show reduced urinary PPi excretion (Baumann et al. 1977; Wikström et al. 1983; Roberts et al. 1992) and, in a group of 107 patients with recurrent calcium stones, 48% had reduced urinary PPi:creatinine ratios compared with control subjects (Laminski et al. 1990).
As already noted, PPi directly inhibits hydroxyapatite crystal growth (Jung et al. 1973). In vitro PPi at concentrations similar to those in normal urine (30 µM) effectively prevents crystallization of hydroxyapatite in artificial urines (Grases et al. 2000; March et al. 2001). However, PPi is not the only inhibitor of crystallization. Other inhibitors include citrate, phytate, magnesium, glycosaminoglycans and polyanionic proteins, including uromodulin (Tamm-Horsfall protein) and osteopontin. Osteopontin is synthesized within rat and human kidney cells and is excreted in urine. It is normally present at the apical surface of the distal tubule in normal cells, but its synthesis is further increased following toxic or ischaemic stress (Verstrepen et al. 2001; Verhulst et al. 2002). Some of these crystallization inhibitors may also act synergistically; for example, PPi and citrate have been shown to have a synergistic effect in artificial urine in preventing hydroxyapatite formation (Costa-Bauza et al. 2002) and similarly, molecular modelling studies suggest that there may be additive effects on control of oxalate crystal growth with more than one inhibitor (Qiu et al. 2004). Taken together, this evidence strongly suggests that urinary PPi is capable of inhibiting urinary calcification at naturally occurring PPi concentrations in the urine, and its effect may be augmented by other crystallization inhibitors.
Sources of pyrophosphate in the kidney
Pyrophosphate is present in plasma at a concentration of 1–6 µM (Russell, 1976), mainly arising from liver metabolism (Rachow & Ryan, 1988). Intravenous 32PPi is rapidly hydrolysed in plasma, with PPi also being filtered at the glomerulus and subject to further hydrolysis within the kidney; only < 5% of intravenous 32PPi appears in urine (Jung et al. 1970), whilst the clearance ratio of PPi to creatinine was 0.08 in man (Russell et al. 1976).
As in bone, the kidney expresses alkaline phosphatases which hydrolyse PPi to inorganic phosphate. Both the intestinal form of alkaline phosphatase and the tissue non-specific form of alkaline phosphatase (TNAP) are present in kidney (Nouwen & De Broe, 1994). ‘Intestinal’ alkaline phosphatase is restricted to the pars recta (S3) of the proximal tubule, whilst TNAP is expressed along the proximal tubule in S1, S2 and S3 segments (Nouwen & De Broe, 1994). The proximal location of these alkaline phosphatase isozymes ensures that the majority of PPi delivered by glomerular filtration will be rapidly hydrolysed (Fig. 2). The physiologically important increase in urinary PPi after ingestion of orthophosphate may result from inhibition of PPi hydrolysis (Russell et al. 1976).
Within the kidney, extracellular PPi may originate from sources other than glomerular filtration (Fig. 2). Adenosine triphosphate has been detected at various locations along the rat tubule lumen (Vekaria et al. 2006b), where it may be secreted by proximal tubular cells in response to flow stimuli (Juul Jensen et al. 2007). It is then rapidly subjected to enzymatic degradation (Vekaria et al. 2006a) by extracellularly located nucleoside triphosphate diphosphohydrolases (NTPDs), producing AMP and PPi from the hydrolysis of ATP. The NTPD isozymes 2 and 3 are expressed in the thick ascending limb and distal tubule of the rat nephron, with NTPD3 also being expressed in the cortical and outer medullary collecting ducts. The isoenzymes NTPD1, 2 and 3 are all expressed in the inner medullary collecting ducts (Vekaria et al. 2006a). The NPP ectoenzymes, mentioned earlier (in the subsection Pyrophosphate in bone and joint mineralization), are present in the kidney and are also capable of generating PPi from ATP or other nucleotide triphosphates. The ectoenzyme NPP1 (formerly known as PC-1) has a key role in normal bone mineralization, as noted above, and is highly expressed on the basolateral membrane of murine distal tubules (Harahap & Goding, 1988), possessing a basolateral targeting signal consistent with this site of expression (Goding et al. 2003). In contrast, NPP3 is highly expressed in the apical membrane of the murine proximal tubule (Goding et al. 2003; Vekaria et al. 2006a). Renal tubules are thus able to generate PPi from a substrate such as extracellular ATP in both the luminal compartment and the interstitial compartment (in the distal tubule). It should be noted that local PPi concentrations within the proximal tubule from NPP3 action or from glomerular filtration are likely to be low, determined by alkaline phosphatase activities. The result is that the majority of ATP-derived PPi in the distal nephron segments will have been produced locally (see Fig. 2).
By far the largest source of PPi generation is as a product of intracellular reactions. The ANK protein transports PPi across the membrane, and Ho et al. (2000) demonstrated, using Northern blotting, that ank mRNA is expressed in many mouse tissues other than joints, including heart, brain, liver, spleen, lung and muscle, but importantly also kidney. The pathological effect of abnormal ANKH function on bones and joints is accepted, as described above (in the subsection Pyrophosphate in bone and joint mineralization), and we can now postulate a similar role for ANKH in suppressing inappropriate mineralization within the urinary system. Indeed, mutant ank/ank mice exhibit nephrocalcinosis (Ho et al. 2000). Similarities between kidney and joints in this regard include the fact that both have cells expressing ANK where extracellular PPi is present, and both have an important need to prevent or to regulate crystal formation in the face of a crystal-inducing environment.
Localization of ANK in the kidney
Expression of ANK has now been confirmed by reverse transcriptase-polymerase chain reaction in mouse kidney and in the model collecting duct cell line, mIMCD-3 (Carr et al. 2007). Immunohistochemistry of mouse kidney sections showed that ANK staining was evident in cortical collecting ducts when identified by costaining with aquaporin-2 (Carr et al. 2007). Staining was not observed in the rest of the nephron, including all segments of the proximal tubule, although there was weak staining of glomeruli. Expression of ANK is therefore prominent in those segments of the nephron downstream from the alkaline phosphatase-expressing proximal segments (Fig. 2).
In the mIMCD-3 cell line, ANK has been shown by immunocytochemistry to be present at both the apical and the basolateral membranes (Carr et al. 2007). Overexpression of an ANK–GFP (Green Fluorescent Protein) fusion protein in mIMCD-3 cells demonstrated colocalization with both the endoplasmic reticulum and mitochondria (Carr et al. 2007). The role of ANK within cells is unclear but may involve Ca2+ sequestration. An N-terminal GFP-tagged construct containing the inactivating mutation G440X, of mutant ank/ank mice, resulted in disruption of ANK–GFP traffic to the cell membrane with retention within the endoplasmic reticulum/Golgi apparatus. Mitochondrial localization was unaffected (Carr et al. 2007). In mouse kidney sections, ANK antibody staining revealed that there was both apical and basolateral ANK staining of both principal cells (aquaporin-2 positive) and intercalated cells (aquaporin-2 negative) in the cortical collecting ducts (Carr et al. 2007). It seems likely, therefore, that ANK-mediated PPi transport across both apical and basolateral membranes will occur and that locally generated PPi may participate in minimizing hydroxyapatite nidus formation within both the renal interstitium and the tubule lumen (Fig. 2).
Scanning the ANK protein for potential serine/threonine phosphorylation sites and combining this with transmembrane topology (10 or 12 segments, as suggested by Ho et al. 2000 and Nurnberg et al. 2001, respectively) indicates multiple potential cytoplasmic sites for phosphorylation mediated by protein kinase A. The subcellular distribution of ANK overlaps with that of aquaporin-2 (Carr et al. 2007) in principal cells, which suggests that the overall activity and perhaps membrane traffic of both proteins is co-ordinated. In a state of systemic dehydration, arginine vasopressin activates V2 receptors, causing an increase in adenylate cyclase activity. This will not only increase cAMP but will also increase intracellular PPi as a substrate for ANK-mediated transport. Evidence for acute regulation of ANK transport function should now be sought.
Pyrophosphate, ANK and their role in renal stone disease
The distinction and relationship between calcium salt deposition within the kidney (nephrocalcinosis) and renal stone disease (nephrolithiasis) remains to be precisely defined. Nephrocalcinosis describes the effect of a heterogeneous group of diseases which cause an increase in the calcium content of the kidney, with many of these now localized to specific mutations often involving tubular transport (reviewed by Sayer et al. 2004). The location of the initial calcium deposits may indicate separate pathophysiological entities. Interstitial nephrocalcinosis at the renal papilla gives rise to Randall's plaques, which may eventually rupture through the papillary epithelium to form stones within the renal calyces (Evan et al. 2006). Tubular nephrocalcinosis, in contrast, results in intratubular deposits that may block urine flow directly (Verkoelen & Verhulst, 2007) and can lead to a reduction in renal function. This process has been noted in conditions such as primary hyperoxaluria, Sjögren's syndrome, renal transplants after 1 year and Dent's disease. In Dent's disease, a mutation of CLCN5, encoding a renal Cl––H+ ion exchanger, disrupts receptor-mediated endocytosis, which ultimately leads to hypercalciuria (Jentsch et al. 2005). Calcium deposits in CLCN5 knock-out mice accumulate within the lumen of the collecting ducts, blocking urine flow (Cebotaru et al. 2005). Despite increasing knowledge of these renal calcification mechanisms, it is not yet possible to predict the mechanism of nephrocalcinosis/nephrolithiasis in most clinical cases.
The unexpected expression of ANK and its localization within the nephron relative to alkaline phosphatase and NTPD/NPP enzymes suggest that the source of urinary PPi is the distal tubule. Furthermore, the presence of ANK in the vasopressin-sensitive cortical collecting duct suggests a link to urinary concentration. Disruption of intrarenal PPi metabolism and output would impact on both interstitial and tubular calcium crystal deposition.
Ho et al. (2000) demonstrated in mice that inactivation of ANK not only disrupts skeletal mineralization, but also causes renal calcification. In contrast, the phenotype of disordered ANKH gene function in the human kidney is largely unexplored. If ANKH is mutated, might we expect a clinical correlation between kidney stones and apatite deposition? In spondyloarthritides, such as ankylosing spondylitis, large amounts of apatite are deposited (Sampson et al. 1991), and the mutant ank/ank mouse has been regarded as a valid model of this (Mahowald et al. 1988). Polymorphisms in two different regions of the ANKH gene were found to be associated with ankylosing spondylitis (Tsui et al. 2005), although this linkage remains controversial (Timms et al. 2003). A clinical study (Canales et al. 2006) found that there was a higher incidence of kidney stone formation in patients with spondyloarthritides compared with rheumatoid arthritis patients (who do not experience apatite deposition) as control subjects, even after correcting for drug use and other stone risk factors. They suggest that this makes spondyloarthropathy an independent risk factor for kidney stones.
Conclusion
Recent studies have now conclusively implicated a physiological role for ANK in regulating tissue calcification in both mice and humans. There are numerous structural and functional parallels between osteoblast/chondrocyte mineralization and the renal tubule, where ANK may significantly contribute to prevent calcification. The importance of local PPi to renal calcification and idiopathic renal stone disease now needs to be determined. Elucidation of these mechanisms may lead to new therapeutic strategies for this common, recurrent and economically important disease.
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Baumann JM, Bisaz S, Felix R, Fleisch H, Ganz U & Russell RG (1977). The role of inhibitors and other factors in the pathogenesis of recurrent calcium-containing renal stones. Clin Sci Mol Med 53, 141–148.[Medline]
Canales BK, Leonard SM, Singh JA, Orzano IM, Zimmermann B, Weiland D, Monga M & Krug HE (2006). Spondyloarthropathy: an independent risk factor for kidney stones. J Endourol 20, 542–546.[CrossRef][Medline]
Carr G, Sayer JA & Simmons NL (2007). Expression and localisation of the pyrophosphate transporter, ANK, in murine kidney cells. Cell Physiol Biochem 20, 507–516.[CrossRef][Medline]
Cebotaru V, Kaul S, Devuyst O, Cai H, Racusen L, Guggino WB & Guggino SE (2005). High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease. Kidney Int 68, 642–652.[CrossRef][Medline]
Costa-Bauza A, Barcelo C, Perello J & Grases F (2002). Synergism between the brushite and hydroxyapatite urinary crystallization inhibitors. Int Urol Nephrol 34, 447–451.[CrossRef][Medline]
Costa-Bauza A, Isern B, Perello J, Sanchis P & Grases F (2005). Factors affecting the regrowth of renal stones in vitro: a contribution to the understanding of renal stone development. Scand J Urol Nephrol 39, 194–199.[CrossRef][Medline]
Evan AP, Lingeman JE, Coe FL, Parks JH, Bledsoe SB, Shao Y, Sommer AJ, Paterson RF, Kuo RL & Grynpas M (2003). Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J Clin Invest 111, 607–616.[CrossRef][Medline]
Evan A, Lingeman J, Coe FL & Worcester E (2006). Randall's plaque: pathogenesis and role in calcium oxalate nephrolithiasis. Kidney Int 69, 1313–1318.[Medline]
Fleisch H & Bisaz S (1962). Isolation from urine of pyrophosphate, a calcification inhibitor. Am J Physiol 203, 671–675.
Goding JW, Grobben B & Slegers H (2003). Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Biochim Biophys Acta 1638, 1–19.[Medline]
Grases F, Ramis M & Costa-Bauza A (2000). Effects of phytate and pyrophosphate on brushite and hydroxyapatite crystallization. Comparison with the action of other polyphosphates. Urol Res 28, 136–140.[CrossRef][Medline]
Gurley KA, Chen H, Guenther C, Nguyen ET, Rountree RB, Schoor M & Kingsley DM (2006a). Mineral formation in joints caused by complete or joint-specific loss of ANK function. J Bone Miner Res 21, 1238–1247.[CrossRef][Medline]
Gurley KA, Reimer RJ & Kingsley DM (2006b). Biochemical and genetic analysis of ANK in arthritis and bone disease. Am J Hum Genet 79, 1017–1029.[CrossRef][Medline]
Harahap AR & Goding JW (1988). Distribution of the murine plasma cell antigen PC-1 in non-lymphoid tissues. J Immunol 141, 2317–2320.[Abstract]
Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R & Millan JL (2004). Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. Am J Pathol 164, 1199–1209.
Ho AM, Johnson MD & Kingsley DM (2000). Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289, 265–270.
Jensen ME, Odgaard E, Christensen MH, Praetorius HA & Leipziger J (2007). Flow-Induced [Ca2+]i increase depends on nucleotide release and subsequent purinergic signaling in the intact nephron. J Am Soc Nephrol 18, 2062–2070.
Jentsch TJ, Poet M, Fuhrmann JC & Zdebik AA (2005). Physiological functions of CLC Cl– channels gleaned from human genetic disease and mouse models. Annu Rev Physiol 67, 779–807.[CrossRef][Medline]
Jung A, Bisaz S & Fleisch H (1973). The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif Tissue Res 11, 269–280.[Medline]
Jung A, Russel RG, Bisaz S, Morgan DB & Fleisch H (1970). Fate of intravenously injected pyrophosphate-32P in dogs. Am J Physiol 218, 1757–1764.
Laminski NA, Meyers AM, Sonnekus MI & Smyth AE (1990). Prevalence of hypocitraturia and hypopyrophosphaturia in recurrent calcium stone formers: as isolated defects or associated with other metabolic abnormalities. Nephron 56, 379–386.[Medline]
Mahowald ML, Krug H & Taurog J (1988). Progressive ankylosis in mice. An animal model of spondylarthropathy. I. Clinical and radiographic findings. Arthritis Rheum 31, 1390–1399.[CrossRef][Medline]
March JG, Simonet BM & Grases F (2001). Determination of pyrophosphate in renal calculi and urine by means of an enzymatic method. Clin Chim Acta 314, 187–194.[CrossRef][Medline]
Nouwen EJ & De Broe ME (1994). Human intestinal versus tissue-nonspecific alkaline phosphatase as complementary urinary markers for the proximal tubule. Kidney Int Suppl 47, S43–S51.[Medline]
Nurnberg P, Thiele H, Chandler D, Hohne W, Cunningham ML, Ritter H, Leschik G, Uhlmann K, Mischung C, Harrop K, Goldblatt J, Borochowitz ZU, Kotzot D, Westermann F, Mundlos S, Braun HS, Laing N & Tinschert S (2001). Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet 28, 37–41.[CrossRef][Medline]
Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, Dixey J, Gillet P, Loeuille D, McGrath R, Reginato A, Shiang R, Wright G, Netter P, Williams C & Kingsley DM (2002). Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet 71, 933–940.[CrossRef][Medline]
Qiu SR, Wierzbicki A, Orme CA, Cody AM, Hoyer JR, Nancollas GH, Zepeda S & De Yoreo JJ (2004). Molecular modulation of calcium oxalate crystallization by osteopontin and citrate. Proc Natl Acad Sci U S A 101, 1811–1815.
Rachow JW & Ryan LM (1988). Inorganic pyrophosphate metabolism in arthritis. Rheum Dis Clin North Am 14, 289–302.[Medline]
Roberts NB, Dutton J, Helliwell T, Rothwell PJ & Kavanagh JP (1992). Pyrophosphate in synovial fluid and urine and its relationship to urinary risk factors for stone disease. Ann Clin Biochem 29, 529–534.[Medline]
Russell RG (1976). Metabolism of inorganic pyrophosphate (PPi). Arthritis Rheum 19 (Suppl. 3), 465–478.[CrossRef][Medline]
Russell RG, Bisaz S & Fleisch H (1976). The influence of orthophosphate on the renal handling of inorganic pyrophosphate in man and dog. Clin Sci Mol Med 51, 435–443.[Medline]
Ryan LM (2001). The ank gene story. Arthritis Res 3, 77–79.[CrossRef][Medline]
Sampson HW, Davis RW & Dufner DC (1991). Spondyloarthropathy in progressive ankylosis mice: ultrastructural features of the intervertebral disk. Acta Anat (Basel) 141, 36–41.[Medline]
Sayer JA, Carr G & Simmons NL (2004). Nephrocalcinosis: molecular insights into calcium precipitation within the kidney. Clin Sci (Lond) 106, 549–561.[Medline]
Terkeltaub RA (2001). Inorganic pyrophosphate generation and disposition in pathophysiology. Am J Physiol Cell Physiol 281, C1–C11.
Timms AE, Zhang Y, Bradbury L, Wordsworth BP & Brown MA (2003). Investigation of the role of ANKH in ankylosing spondylitis. Arthritis Rheum 48, 2898–2902.[CrossRef][Medline]
Tsui HW, Inman RD, Paterson AD, Reveille JD & Tsui FW (2005). ANKH variants associated with ankylosing spondylitis: gender differences. Arthritis Res Ther 7, R513–R525.[CrossRef][Medline]
Vekaria RM, Shirley DG, Sevigny J & Unwin RJ (2006a). Immunolocalization of ectonucleotidases along the rat nephron. Am J Physiol Renal Physiol 290, F550–F560.
Vekaria RM, Unwin RJ & Shirley DG (2006b). Intraluminal ATP concentrations in rat renal tubules. J Am Soc Nephrol 17, 1841–1847.
Verhulst A, Persy VP, Van Rompay AR, Verstrepen WA, Helbert MF & De Broe ME (2002). Osteopontin synthesis and localization along the human nephron. J Am Soc Nephrol 13, 1210–1218.
Verkoelen CF & Verhulst A (2007). Proposed mechanisms in renal tubular crystal retention. Kidney Int 72, 13–18.[CrossRef][Medline]
Verstrepen WA, Persy VP, Verhulst A, Dauwe S & De Broe ME (2001). Renal osteopontin protein and mRNA upregulation during acute nephrotoxicity in the rat. Nephrol Dial Transplant 16, 712–724.
Whyte MP (1994). Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15, 439–461.[CrossRef][Medline]
Wikström B, Danielson BG, Ljunghall S, McGuire M & Russell RGG (1983). Urinary pyrophosphate excretion in renal stone formers with normal and impaired renal acidification. World J Urol 1, 150–154.[CrossRef]
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