Inefficient Chronic Activation of Parietal Cells in Ae2−/− Mice

Recalde, Sergio; Muruzábal, Francisco; Looije, Norbert; Kunne, Cindy; Burrell, Marı́a A.; Sáez, Elena; Martı́nez-Ansó, Eduardo; Salas, January T.; Mardones, Pablo; Prieto, Jesús; Medina, Juan F.; Elferink, Ronald P.J. Oude

doi:10.2353/ajpath.2006.051096

Cited by 41 publications

(36 citation statements)

References 44 publications

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“…The Ae2 exchanger in the wild-type mice was localised in the basolateral membranes of the maturation ameloblasts similar to parietal cells in the gastric gland (Recalde et al, 2006) and in osteoclasts (Jansen, DC et al, 2007, personal communication). Both cell types secrete large amounts of protons, express cytoplasmic CA-II and have a proton pump in their apical membrane.…”

Section: Discussionmentioning

confidence: 99%

The anion exchanger Ae2 is required for enamel maturation in mouse teeth

et al. 2008

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One of the mechanisms by which epithelial cells regulate intracellular pH is exchanging bicarbonate for Cl − . We tested the hypothesis that in ameloblasts the anion exchanger-2 (Ae2) is involved in pH regulation during maturation stage amelogenesis. Quantitative X-ray microprobe mineral content analysis, scanning electron microscopy, histology, micro-computed tomography and Ae2 immunolocalisation analyses were applied to Ae2-deficient and wild-type mouse mandibles. Immunolocalisation of Ae2 in wild-type mouse incisors showed a very strong expression of Ae2 in the basolateral membranes of the maturation stage ameloblasts. Strikingly, zones of contiguous ameloblasts were found within the maturation stage in which Ae2 expression was extremely low as opposed to neighbouring cells. Maturation stage ameloblasts of the Ae2 a,b −/− mice failed to stain for Ae2 and showed progressive disorganisation as enamel development advanced. Maturation stage enamel of the Ae2 a,b −/− mice contained substantially less mineral and more protein than wild-type enamel as determined by quantitative X-ray microanalysis. Incisor enamel was more severely affected than molar enamel. Scanning electron microscopy revealed that the rod-inter-rod structures of the Ae2 a,b −/− mice incisor enamel were absent. Mineral content of dentine and bone of Ae2 a,b −/− mice was not significantly different from wild-type mice. The enamel from knockout mouse teeth wore down much faster than that from wild-type litter mates. Basolateral bicarbonate secretion via the anionic exchanger Ae2 is essential for mineral growth in the maturation stage enamel. The observed zonal expression of Ae2 in the maturation stage ameloblasts is in line with a model for cyclic proton secretion during maturation stage amelogenesis.

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Section: Discussionmentioning

confidence: 99%

The anion exchanger Ae2 is required for enamel maturation in mouse teeth

et al. 2008

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“…5E). Because SLC4A2 promotes gastric acid secretion (13,15) and osteoclasts secrete protons to resorb bone, the ability of Slc4a2 Ϫ/Ϫ cells to form an acidic, extracellular compartment was tested. Whereas WT osteoclasts formed large, acridine orange-positive discs, indicating acidic extracellular resorption pits, Slc4a2 Ϫ/Ϫ cells did not (Fig.…”

Section: Slc4a2 Is Required For Bone Resorption and Vacuolar Acidificmentioning

confidence: 99%

HCO ₃ ⁻ /Cl ⁻ anion exchanger SLC4A2 is required for proper osteoclast differentiation and function

Glimcher

Aliprantis

2008

Proc. Natl. Acad. Sci. U.S.A.

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As the only cell capable of bone resorption, the osteoclast is a central mediator of skeletal homeostasis and disease. To efficiently degrade mineralized tissue, these multinucleated giant cells secrete acid into a resorption lacuna formed between their apical membrane and the bone surface. For each proton pumped into this extracellular compartment, one bicarbonate ion remains in the cytoplasm. To prevent alkalinization of the cytoplasm, a basolateral bicarbonate/chloride exchanger provides egress for intracellular bicarbonate. However, the identity of this exchanger is unknown. Here, we report that the bicarbonate/chloride exchanger, solute carrier family 4, anion exchanger, member 2 (SLC4A2), is up-regulated during osteoclast differentiation. Suppression of Slc4a2 expression by RNA interference inhibits the ability of RAW cells, a mouse macrophage cell line, to differentiate into osteoclasts and resorb mineralized matrix in vitro. Accordingly, Slc4a2-deficient mice fail to remodel the primary, cartilaginous skeletal anlagen. Abnormal multinucleated giant cells are present in the bone marrow of Slc4a2-deficient mice. Though these cells express the osteoclast markers CD68, cathepsin K, and NFATc1, compared with their wild-type (WT) counterparts they are larger, fail to express tartrate-resistant acid phosphatase (TRAP) activity, and display a propensity to undergo apoptosis. In vitro Slc4a2-deficient osteoclasts are unable to resorb mineralized tissue and cannot form an acidified, extracellular resorption compartment. These data highlight SLC4A2 as a critical mediator of osteoclast differentiation and function in vitro and in vivo.one is a remarkable biomaterial composed of organic and inorganic molecules that remodels to preserve structural integrity and adapt to stress. Two cells execute this process: the osteoblast and osteoclast, which synthesize and catabolize bone respectively. An imbalance between osteoclast and osteoblast activity perturbs bone quality, leading to fractures or skeletal deformities (1, 2).The osteoclast is a multinucleated giant cell that differentiates from myeloid precursors under the influence of the osteoblastderived cytokines, macrophage-colony stimulating factor (MCSF) and receptor activator for nuclear factor-B ligand (RANKL). This process is controlled by the transcription factor, nuclear factor of activated T cells c1 (NFATc1), which is induced by RANKL and governs the expression of genes necessary for osteoclast formation and function (3). After differentiation, the osteoclast polarizes, forming a resorption lacuna between its apical membrane and the mineralized bone surface. Within this space, the osteoclast secretes enzymes, as well as acid, via an apical, H ϩ -vacuolar ATPase. The low pH of the resorption lacuna activates these proteolytic enzymes and promotes dissolution of crystalline calcium phosphate. To maintain electroneutrality, a parallel chloride/proton antiporter releases a chloride ion with each proton (4). In humans and mice, mutations in either the proton pump (T...

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“…The grossly normal Ae2 a,b -/-mouse exhibits male infertility associated with testicular dysplasia (Medina et al, 2003). However, the Ae2 a,b -/-mouse is also hypomorphic for other phenotypes of the complete knockout mouse, including osteopetrosis (Josephsen et al, 2009), failure of dental enamelization (Lyaruu et al, 2008), and reduced stimulated gastric acid secretion in the setting of preserved basal acid secretion, accompanied by chronic, mild mucosal degeneration (Recalde et al, 2006).…”

Section: Disease Phenotypes Associated With Slc4a2/ae2 and Slc4a3/ae3mentioning

confidence: 99%

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Alper

2009

Journal of Experimental Biology

194

220

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SUMMARY Plasmalemmal Cl–/HCO3–exchangers are encoded by the SLC4 and SLC26 gene superfamilies, and function to regulate intracellular pH,[Cl–] and cell volume. The Cl–/HCO3– exchangers of polarized epithelial cells also contribute to transepithelial secretion and reabsorption of acid–base equivalents and Cl–. This review focuses on Na+-independent electroneutral Cl–/HCO3– exchangers of the SLC4 family. Human SLC4A1/AE1 mutations cause the familial erythroid disorders of spherocytic anemia, stomatocytic anemia and ovalocytosis. A largely discrete set of AE1 mutations causes familial distal renal tubular acidosis. The Slc4a2/Ae2–/– mouse dies before weaning with achlorhydria and osteopetrosis. A hypomorphic Ae2–/– mouse survives to exhibit male infertility with defective spermatogenesis and a syndrome resembling primary biliary cirrhosis. A human SLC4A3/AE3 polymorphism is associated with seizure disorder, and the Ae3–/– mouse has increased seizure susceptibility. The transport mechanism of mammalian SLC4/AE polypeptides is that of electroneutral Cl–/anion exchange,but trout erythroid Ae1 also mediates Cl– conductance. Erythroid Ae1 may mediate the DIDS-sensitive Cl– conductance of mammalian erythrocytes, and, with a single missense mutation, can mediate electrogenic SO42–/Cl– exchange. AE1 trafficking in polarized cells is regulated by phosphorylation and by interaction with other proteins. AE2 exhibits isoform-specific patterns of acute inhibition by acidic intracellular pH and independently by acidic extracellular pH. In contrast, AE2 is activated by hypertonicity and, in a pH-independent manner, by ammonium and by hypertonicity. A growing body of structure–function and interaction data, together with emerging information about physiological function and structure, is advancing our understanding of SLC4 anion exchangers.

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Inefficient Chronic Activation of Parietal Cells in Ae2−/− Mice

Cited by 41 publications

References 44 publications

The anion exchanger Ae2 is required for enamel maturation in mouse teeth

The anion exchanger Ae2 is required for enamel maturation in mouse teeth

HCO ₃ ⁻ /Cl ⁻ anion exchanger SLC4A2 is required for proper osteoclast differentiation and function

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

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Inefficient Chronic Activation of Parietal Cells in Ae2−/− Mice

Cited by 41 publications

References 44 publications

The anion exchanger Ae2 is required for enamel maturation in mouse teeth

The anion exchanger Ae2 is required for enamel maturation in mouse teeth

HCO 3 − /Cl − anion exchanger SLC4A2 is required for proper osteoclast differentiation and function

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

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HCO ₃ ⁻ /Cl ⁻ anion exchanger SLC4A2 is required for proper osteoclast differentiation and function