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Characteristics of ClC7 Cl− channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells

  • Ion Channels, Receptors and Transporters
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Abstract

ClC7 Cl− channels (Clcn7) are crucial for osteoclastic bone resorption and have heterozygous mutation in autosomal osteopetrosis type II (ADO II) patients. Although extracellular acidification is known to induce ClC7 Cl− currents in Clcn7-transfected oocytes, other characteristics of this acid-induced Cl− current, as well as the effects of mutant Clcn7 in ADO II, remain to be determined. The present study showed that extracellular acidification evoked outward Cl− currents in mouse osteoclasts. Expression of wild-type human Clcn7 in HEK293 cells also induced a significant increase in acid-activated Cl− currents. These acid-activated Cl− currents were independent of intracellular acidification and [Ca2+] i increase. HEK293 cells with the Clcn7 mutation associated with ADO II at G215R did not display these Cl− currents. These results suggest that osteoclastic ClC7 Cl− channels are activated under extracellar acidification and suppressed in Clcn7 mutant associated with ADO II during bone resorption.

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References

  1. Auzanneau C, Thoreau V, Kitzis A (2003) Becq FA novel voltage-dependent chloride current activated by extracellular acidic pH in cultured rat Sertoli cells. J Biol Chem 278:19230–19236

    Article  PubMed  CAS  Google Scholar 

  2. Benichou O, Cleiren E, Gram J, Bollerslev J, de Vernejoul MC, Van Hul W (2001) Mapping of autosomal dominant osteopetrosis type II (Albers-Schönberg disease) to chromosome 16p13.3. Am J Hum Genet 69:647–654

    Article  PubMed  CAS  Google Scholar 

  3. Blair HC, Teitelbaum SL, Ghiselli R, Gluck S (1989) Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 245:855–857

    Article  PubMed  CAS  Google Scholar 

  4. Bollerslev J (1989) Autosomal dominant osteopetrosis: bone metabolism and epidemiological, clinical, and hormonal aspects. Endcr Rev 10:45–67

    Article  CAS  Google Scholar 

  5. Brandt S, Jentsch TJ (1995) ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family. FEBS Lett 377:15–20

    Article  PubMed  CAS  Google Scholar 

  6. Brockstedt H, Bollerslev J, Melsen F, Mosekilde L (1996) Cortical bone remodeling in autosomal dominant osteopetrosis: a study of two different phenotypes. Bone 18:67–72

    Article  PubMed  CAS  Google Scholar 

  7. Chu K, Snyder R, Econs MJ (2006) Disease status in autosomal dominant osteopetrosis type 2 is determined by osteoclastic properties. J Bone Miner Res 21:1089–1097

    Article  PubMed  CAS  Google Scholar 

  8. Cleiren E, Benuchou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte WP, Yoneyama T, deVernejoul MC, Van Hul W (2001) Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 10:2861–2867

    Article  PubMed  CAS  Google Scholar 

  9. Daniels RJ, Peden JF, Lloyd C, Horsley SW, Clark K, Tufarelli C, Kearney L, Buckle VJ, Doggett NA, Flint J, Higgs DR (2001) Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16. Hum Mol Genet 10:339–352

    Article  PubMed  CAS  Google Scholar 

  10. Diewald L, Rupp J, Dreger M, Hucho F, Gillen C, Nawrath H (2002) Activation by acidic pH of CLC-7 expressed in oocytes from Xenopus laevis. Biochem Biophys Res Commun 291:421–424

    Article  PubMed  CAS  Google Scholar 

  11. Duan D, Winter C, Cowley S, Hume JR, Horowitz B (1997) Molecular identification of a volume-regulated chloride channel. Nature 390:417–421

    Article  PubMed  CAS  Google Scholar 

  12. Dutzler A, Campbell EB, Cadene M, Chait BT, MacKinnon R (2002) X-ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity. Nature 415:287–294

    Article  PubMed  CAS  Google Scholar 

  13. Forgac M (1989) Structure and function of vacuolar class of ATP-driven proton pumps. Physiol Rev 69:765–796

    PubMed  CAS  Google Scholar 

  14. Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinum M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A (2000) Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25:343–346

    Article  PubMed  CAS  Google Scholar 

  15. Graves AR, Curran PK, Smith CL, Mindell JA (2008) The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature 453:788–792

    Article  PubMed  CAS  Google Scholar 

  16. Henriksen K, Gram J, Schaller S, Dahl BH, Dziegiel MH, Bollerslev J, Karsdal MA (2004) Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis typeII. Am J Pathol 164:1537–1545

    PubMed  CAS  Google Scholar 

  17. Kajiya H, Okamoto F, Li JP, Nakao A, Okabe K (2006) Expression of mouse osteoclast K-Cl co-transporter-1 and its role during bone resorption. J Bone Miner Res 21:984–992

    Article  PubMed  CAS  Google Scholar 

  18. Kasper D, Planells-Cases R, Fuhrmann JC, Scheel O, Zeitz O, Klaus R, Schmitt A, Poet M, Steinfeld R, Schweizer M, Kornak U, Jentsch TJ (2005) Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J 24:1079–1091

    Article  PubMed  CAS  Google Scholar 

  19. Kelly ME, Dixon SJ, Sims SM (1994) Outwardly rectifying chloride current in rabbit osteoclasts is activated by hyposmotic stimulation. J Physiol 475:377–389

    PubMed  CAS  Google Scholar 

  20. Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, Friendrich W, Delling G, Jentsch TJ (2001) Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104:205–215

    Article  PubMed  CAS  Google Scholar 

  21. Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C (2000) Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 9:2059–2063

    Article  PubMed  CAS  Google Scholar 

  22. Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC (2006) ClC-7 requires Ostm1 as a β-subunit to support bone resorption and lysosomal function. Nature 440:220–223

    Article  PubMed  CAS  Google Scholar 

  23. Ludewig U, Pusch M, Jentsch TJ (1996) Two physically distinct pores in the dimeric ClC-0 chloride channel. Nature 383:340–343

    Article  PubMed  CAS  Google Scholar 

  24. Okamoto F, Kajiya H, Fukushima H, Jimi E, Okabe K (2004) Prostaglandin E2 activates outwardly rectifying Cl- channels via a cAMP-dependent pathway and reduces cell motility in rat osteoclasts. Am J Physiol Cell Physiol 287:C114–C124

    Article  PubMed  CAS  Google Scholar 

  25. Picollo A (2005) Pusch M (2005) chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature 436:420–423

    Article  PubMed  CAS  Google Scholar 

  26. Reddy SV, Devlin RD, Menna C, Nishumura R, Choi SJ, Yoneda T, Roodman GD (1998) Isolation and characterization of a cDNA clone encoding a novel peptide (OSF) that enhances osteoclast formation and bone resorption. J Cell Physiol 177:636–645

    Article  PubMed  CAS  Google Scholar 

  27. Schaller S, Henriksen K, Sveigaard C, Heegaard AM, Helix N, Stahlhut M, Ovejero MC, Johansen JV, Solberg H, Andersen TL, Hougaard D, Berryman M, Shiϕdt CB, Sϕrensen BH, Lichtenberg J, Christophersen P, Foged NT, Delaisse JM, Engsig MT, Karsdal MA (2004) The chloride channel inhibitor NS3736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 19:1144–1153

    Article  PubMed  CAS  Google Scholar 

  28. Schmidt-Rose T, Jentsch TJ (1997) Transmembrane topology of a CLC chloride channel. Proc Natl Acad Sci U S A 94:7633–7638

    Article  PubMed  CAS  Google Scholar 

  29. Semba I, Ishigami T, Sugihara K, Kitano M (2000) Higher osteoclastic demineralization and highly mineralized cement lines with osteocalcin deposition in a mandibular cortical bone of autosomal dominant osteopetrosis type II: ultrastructural and undecalcified histological investigations. Bone 27:389–395

    Article  PubMed  CAS  Google Scholar 

  30. Silver IA, Murrills RJ, Etherington DJ (1988) Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res 175:266–276

    Article  PubMed  CAS  Google Scholar 

  31. Takahashi N, Yamada H, Yoshiki S, Roodman GD, Mundy GR, Jones SJ, Boyde A, Suda T (1988) Osteoclasts-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology 122:1373–1382

    Article  PubMed  CAS  Google Scholar 

  32. Tezuka K, Sato T, Kamioka H, Nijiweide PJ, Tanaka K, Matsuo T, Ohta M, Kirihara N, Hakeda Y, Kumegawa M (1992) Identification of osteopontin in isolated rabbit osteoclasts. Biochem Biophys Res Commun 186:911–917

    Article  PubMed  CAS  Google Scholar 

  33. Waguespack SG, Hui SL, White KE, Buckwalter KA, Econs MJ (2002) Measurement of tartrate-resistant acid phosphatase and the brain isoenzyme of creatine kinase accurately diagnoses type II autosomal dominant osteopetrosis but does not identify gene carriers. J Clin Endocrinol Metab 87:2212–2217

    Article  PubMed  CAS  Google Scholar 

  34. Wang GX, Hatton WJ, Wang GL, Zhong J, Yamboliev I, Duan D, Hume JR (2003) Functional effects of novel anti-ClC-3 antibodies on native volume-sensitive osmolyte and anion channels in cardiac and smooth muscle cells. Am J Physiol Heart Circ Physiol 285:H1453–H1463

    PubMed  CAS  Google Scholar 

  35. Yamamoto S, Ehara T (2006) Acidic extracellular pH-activated outwardly rectifying chloride current in mammalian myocytes. Am J Physiol Heart Circ Physiol 290:H1905–H1914

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Dr. S.V. Reddy for the gift of human osteoclast cDNA library and his valuable comments. We would also like to thank Dr. Andreas Carl and Jeremy Williams for editing the English of this manuscript.

Grants

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 17591957 and 19592165) and a Frontier Research Grant.

Conflicts of interest

The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Tamura 2-15-1, Sawara-ku, Fukuoka, 8140193, Japan

    Hiroshi Kajiya, Fujio Okamoto, Kimiko Ohgi, Akihiro Nakao, Hidefumi Fukushima & Koji Okabe

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  1. Hiroshi Kajiya
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  2. Fujio Okamoto
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  3. Kimiko Ohgi
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Correspondence to Hiroshi Kajiya.

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Kajiya, H., Okamoto, F., Ohgi, K. et al. Characteristics of ClC7 Cl− channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells. Pflugers Arch - Eur J Physiol 458, 1049–1059 (2009). https://doi.org/10.1007/s00424-009-0689-4

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