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Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1)

  • Ion channels, receptors and transporters
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Abstract

Calcium is a key component of the bone mineral hydroxyapatite. During osteoclast-mediated bone resorption, hydroxyapatite is dissolved and significant quantities of calcium are released. Several calcium transport systems have previously been identified in osteoclasts, including members of the sodium/calcium exchanger (NCX) family. Expression pattern and physiological role of NCX isoforms in osteoclasts, however, remain largely unknown at the moment. Our data indicate that all three NCX isoforms (NCX1, NCX2, and NCX3) are present in murine osteoclasts. RANKL-induced differentiation of murine osteoclast precursors into mature osteoclasts significantly attenuated the expression of NCX1, while NCX2 and NCX3 expressions were largely unaffected. To study the role of NCX1 during osteoclast differentiation and bone resorption, we crossed mice with exon 11 of the NCX1 gene flanked by loxP sites with cathepsin K-Cre transgenic mice. Mature osteoclasts derived from transgenic mice exhibited an 80–90% reduction of NCX1 protein. In vitro studies indicate that NCX1 is dispensable for osteoclast differentiation, but NCX1-deficient osteoclasts exhibited increased resorptive activity. In line with these in vitro findings, mice with an osteoclast-targeted deletion of the NCX1 gene locus displayed an age-dependent loss of bone mass. Thus, in summary, our data reveal NCX1 as a regulator of osteoclast-mediated bone resorption.

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Acknowledgements

We thank Kenneth Philippson, Department of Physiology, David Geffen School of Medicine, UCLA for NCX1 mutant mice. DGF was supported by the Swiss National Science Foundation (grant nos. 3100A0_135503 and 3100A0_152829) and by a Medical Research Position Award of the Foundation Prof. Dr. Max Cloëtta. OB is supported by a Swiss National Science Foundation professorship grant (PP00P3-133648). This work was further supported by the Swiss National Science Foundation funded National Centers for Competence in Research (NCCR Transcure and NCCR Kidney.CH) to DGF, OB, and WH.

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Authors and Affiliations

  1. Division of Nephrology, Hypertension and Clinical Pharmacology, Bern University Hospital, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland

    Giuseppe Albano & Daniel G. Fuster

  2. Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

    Giuseppe Albano & Daniel G. Fuster

  3. NCCR Transcure, University of Bern, Bern, Switzerland

    Giuseppe Albano, Silvia Dolder, Mark Siegrist, Willy Hofstetter & Daniel G. Fuster

  4. Department of Clinical Research, University of Bern, Bern, Switzerland

    Giuseppe Albano, Silvia Dolder, Mark Siegrist, Willy Hofstetter & Daniel G. Fuster

  5. Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

    Annie Mercier-Zuber, Muriel Auberson, Candice Stoudmann & Olivier Bonny

  6. NCCR Kidney.CH, University of Zürich, Zürich, Switzerland

    Giuseppe Albano, Annie Mercier-Zuber, Muriel Auberson, Candice Stoudmann, Olivier Bonny & Daniel G. Fuster

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  1. Giuseppe Albano
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  2. Silvia Dolder
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  3. Mark Siegrist
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  4. Annie Mercier-Zuber
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  7. Willy Hofstetter
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  8. Olivier Bonny
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  9. Daniel G. Fuster
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Correspondence to Daniel G. Fuster.

Ethics declarations

All animal experiments were in accordance with the Swiss Animal Welfare Law and were approved by the Local Veterinary Authority Bern (Veterinäramt Bern) and Vaud (Office vétérinaire cantonal).

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The authors declare that they have no conflict of interest.

Additional information

Olivier Bonny and Daniel G. Fuster contributed equally.

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Albano, G., Dolder, S., Siegrist, M. et al. Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1). Pflugers Arch - Eur J Physiol 469, 225–233 (2017). https://doi.org/10.1007/s00424-016-1923-5

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  • DOI: https://doi.org/10.1007/s00424-016-1923-5

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