Abstract

Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification (pages 610–612).

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Acknowledgements

We thank O. Winter, M. Dietzmann, C. Erdmann, T.O. Klatte, S. Kessler, G. Arndt and S. Conrad for technical assistance. Moreover, we are grateful to A.S. Kopin (Tufts Medical Center) and G.E. Shull (University of Cincinnati) for providing the Cckbr−/− and Slc4a2+/− mice, respectively. This work was supported by grants from the Deutsche Forschungsgemeinschaft to M.A. (AM103/14-1) and M.B. (BL423/4-3), from the Deutsches Zentrum für Luft- und Raumfahrt within the framework of the E-Rare JTC 2007 to M.A., A.S., U.K., A.T. and A.V., from Telethon to A.T. (GGP06119) and by the NOBEL program from Fondazione Cariplo to A.V.

Author information

Author notes

    • Thorsten Schinke
    •  & Arndt F Schilling

    These authors contributed equally to this work.

Affiliations

  1. Center for Biomechanics and Skeletal Biology, Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Thorsten Schinke
    • , Arndt F Schilling
    • , Anke Baranowsky
    • , Sebastian Seitz
    • , Robert P Marshall
    • , Tilman Linn
    • , Antje K Huebner
    • , Matthias Gebauer
    • , Matthias Priemel
    • , Sandra Perkovic
    • , Florian Barvencik
    • , F Timo Beil
    • , Johannes M Rueger
    •  & Michael Amling
  2. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Michael Blaeker
  3. Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.

    • Ansgar Schulz
    •  & Klaus-Michael Debatin
  4. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Ronald Simon
    • , Jozef Zustin
    •  & Guido Sauter
  5. Institute of Medical Genetics, Charite University Medical Center, Berlin, Germany.

    • Uwe Kornak
  6. Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.

    • Andrea Del Fattore
    •  & Anna Teti
  7. Human Genome Department, Istituto di Tecnologie Biomediche, Italian National Research Council (CNR), Segrate, Italy.

    • Annalisa Frattini
    •  & Anna Villa
  8. Istituto Clinico Humanitas, IRCCS, Rozzano, Italy.

    • Annalisa Frattini
    •  & Anna Villa
  9. Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Thomas Streichert
  10. Institute of Forensic Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Klaus Pueschel

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Correspondence to Michael Amling.

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DOI

https://doi.org/10.1038/nm.1963

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