Cited by 995Bone Metabolism and DiseasesIon channel regulation and functionIon Transport and Channel Regulation

Loss of the ClC-7 Chloride Channel Leads to Osteopetrosis in Mice and Man

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Kornak, Uwe, Kasper, Dagmar, Bösl, Michael R, Kaiser, Edelgard, Schweizer, Michaela, Schulz, Ansgar, Friedrich, Wilhelm, Delling, Günter +1 more·2001·Cell

Abstract

Chloride channels play important roles in the plasma membrane and in intracellular organelles. Mice deficient for the ubiquitously expressed ClC-7 Cl(-) channel show severe osteopetrosis and retinal degeneration. Although osteoclasts are present in normal numbers, they fail to resorb bone because they cannot acidify the extracellular resorption lacuna. ClC-7 resides in late endosomal and lysosomal compartments. In osteoclasts, it is highly expressed in the ruffled membrane, formed by the fusion of H(+)-ATPase-containing vesicles, that secretes protons into the lacuna. We also identified CLCN7 mutations in a patient with human infantile malignant osteopetrosis. We conclude that ClC-7 provides the chloride conductance required for an efficient proton pumping by the H(+)-ATPase of the osteoclast ruffled membrane.

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Crossref · 10.1016/s0092-8674(01)00206-9

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43 of 43 references verified0 citation errors · 0 not checkable

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  • In the ruffled border, V-ATPase helps to acidify the resorption lacuna and enable dissolution of hydroxyapatite crystals.

    “In the ruffled border, there is a vacuolar-type H+-ATPase (V-ATPase), which helps to acidify the resorption lacuna and hence to enable dissolution of hydroxyapatite crystals [20, 100, 101].”
  • The ruffled border membrane allows large vesicle transport, delivery of hydrochloric acid by V-ATPase and CLC-7, and release of lysosomal proteases such as cathepsin K, TRAP, and MMPs.

    “The ruffled border membrane allows large vesicle transport, the delivery of hydrochloric acid (by vacuolar-type H + ATPase186) and chloride ion channel-7 (CLC-7),187 and the release of several lysosomal proteases, such as cathepsin K, TRAP, and MMPs.188”

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Authors
Kornak, U., Kasper, D., Bösl, M. R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W., Delling, G., & Jentsch, T. J.
Affiliations
  • Universität Hamburg (DE)
  • Universität Ulm (DE)
Venue
Cell
Publisher
Elsevier BV
Published
2001-01
Volume
104
Issue
2
Pages
205-215
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2041455826
Cited by
995
References
43
Citations by year
2026: 14 · 2025: 24 · 2024: 24 · 2023: 33 · 2022: 35 · 2021: 34 · 2020: 40 · 2019: 31 · 2018: 35 · 2017: 26 · 2016: 31 · 2015: 43 · 2014: 23 · 2013: 49 · 2012: 34
FWCI
18.16
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
osteopetrosis, malignant infantile osteopetrosis, osteoclasts, bone resorption, H+-ATPase, proton secretion, lysosomes, late endosomes, retinal degeneration, chloride conductance
MeSH terms
Adenosine Triphosphatases, Animals, Bone Development, Bone Resorption, Cells, Cultured, Embryo, Mammalian, Humans, Immunohistochemistry, Nerve Degeneration, Optic Nerve, Osteoclasts, Osteopetrosis, Platelet Membrane Glycoproteins, Recombinant Fusion Proteins, Retina, Retinal Degeneration, RNA, Blotting, Northern, Blotting, Western, Organelles, Antigens, CD, In Situ Hybridization, Sequence Analysis, DNA, Genes, Reporter, Chloride Channels, Microscopy, Confocal, Cell Surface Extensions, Integrin beta3, Mice

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