Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Impaired gastric acidification negatively affects calcium homeostasis and bone mass

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).

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Osteopetrosis (OPT) and osteopetrorickets (OPR) are distinct phenotypes.
Figure 2: Osteoid enrichment in oc/oc mice is caused by hypocalcemia.
Figure 3: Tcirg1 is expressed by parietal cells and involved in gastric acidification.
Figure 4: Osteopetrorickets caused by a combined defect of bone resorption and gastric acidification.
Figure 5: Osteoporotic phenotype of Cckbr−/− mice.
Figure 6: Hypochlorhydria-induced bone loss is prevented by calcium gluconate supplementation.

Similar content being viewed by others

References

  1. Harada, S. & Rodan, G.A. Control of osteoblast function and regulation of bone mass. Nature 423, 349–355 (2003).

    Article  CAS  Google Scholar 

  2. Teitelbaum, S.L. & Ross, F.P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

    Article  CAS  Google Scholar 

  3. Karaplis, A.C. & Goltzman, D. PTH and PTHrP effects on the skeleton. Rev. Endocr. Metab. Disord. 1, 331–341 (2000).

    Article  CAS  Google Scholar 

  4. Kaplan, F.S., August, C.S., Fallon, M.D., Gannon, F. & Haddad, J.G. Osteopetrorickets. The paradox of plenty. Pathophysiology and treatment. Clin. Orthop. Relat. Res. 294, 64–78 (1993).

    Article  Google Scholar 

  5. Taranta, A. et al. Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis. Am. J. Pathol. 162, 57–68 (2003).

    Article  CAS  Google Scholar 

  6. Kirubakaran, C., Ranjini, K., Scott, J.X., Basker, M. & Sridhar, G. Osteopetrorickets. J. Trop. Pediatr. 50, 185–186 (2004).

    Article  Google Scholar 

  7. Del Fattore, A., Cappariello, A. & Teti, A. Genetics, pathogenesis and complications of osteopetrosis. Bone 42, 19–29 (2008).

    Article  CAS  Google Scholar 

  8. Sly, W.S. et al. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N. Engl. J. Med. 313, 139–145 (1985).

    Article  CAS  Google Scholar 

  9. Kornak, U. et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104, 205–215 (2001).

    Article  CAS  Google Scholar 

  10. Lange, P.F., Wartosch, L., Jentsch, T.J. & Fuhrmann, J.C. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature 440, 220–223 (2006).

    Article  CAS  Google Scholar 

  11. Nishi, T. & Forgac, M. The vacuolar H+-ATPases—nature's most versatile proton pumps. Nat. Rev. Mol. Cell Biol. 3, 94–103 (2002).

    Article  CAS  Google Scholar 

  12. Li, Y.P., Chen, W., Liang, Y., Li, E. & Stashenko, P. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat. Genet. 23, 447–451 (1999).

    Article  CAS  Google Scholar 

  13. Scimeca, J.C. et al. The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone 26, 207–213 (2000).

    Article  CAS  Google Scholar 

  14. Marks, S.C. Jr., Seifert, M.F. & Lane, P.W. Osteosclerosis, a recessive skeletal mutation on chromosome 19 in the mouse. J. Hered. 76, 171–176 (1985).

    Article  Google Scholar 

  15. Frattini, A. et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat. Genet. 25, 343–346 (2000).

    Article  CAS  Google Scholar 

  16. Kornak, U. et al. Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis. Hum. Mol. Genet. 9, 2059–2063 (2000).

    Article  CAS  Google Scholar 

  17. Sobacchi, C. et al. The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum. Mol. Genet. 10, 1767–1773 (2001).

    Article  CAS  Google Scholar 

  18. Del Fattore, A. et al. Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J. Med. Genet. 43, 315–325 (2006).

    Article  CAS  Google Scholar 

  19. Banco, R., Seifert, M.F., Marks, S.C. Jr. & McGuire, J.L. Rickets and osteopetrosis: the osteosclerotic (oc) mouse. Clin. Orthop. Relat. Res. 201, 238–246 (1985).

    Google Scholar 

  20. Li, Y.P., Chen, W. & Stashenko, P. Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit. Biochem. Biophys. Res. Commun. 218, 813–821 (1996).

    Article  CAS  Google Scholar 

  21. Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).

    Article  CAS  Google Scholar 

  22. Langhans, N. et al. Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice. Gastroenterology 112, 280–286 (1997).

    Article  CAS  Google Scholar 

  23. Gawenis, L.R. et al. Mice with a targeted disruption of the AE2 Cl/HCO3 exchanger are achlorhydric. J. Biol. Chem. 279, 30531–30539 (2004).

    Article  CAS  Google Scholar 

  24. Wilson, C.J. & Velodi, A. Autosomal recessive osteopetrosis: diagnosis, management, and outcome. Arch. Dis. Child. 83, 449–452 (2000).

    Article  CAS  Google Scholar 

  25. Driessen, G.J. et al. Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 32, 657–663 (2003).

    Article  CAS  Google Scholar 

  26. Frattini, A. et al. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J. Bone Miner. Res. 18, 1740–1747 (2003).

    Article  CAS  Google Scholar 

  27. Kasper, D. et al. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J. 24, 1079–1091 (2005).

    Article  CAS  Google Scholar 

  28. Pangrazio, A. et al. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J. Bone Miner. Res. 21, 1098–1105 (2006).

    Article  CAS  Google Scholar 

  29. Chalhoub, N. et al. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat. Med. 9, 399–406 (2003).

    Article  CAS  Google Scholar 

  30. Kassarjian, Z. & Russell, R.M. Hypochlorhydria: a factor in nutrition. Annu. Rev. Nutr. 9, 271–285 (1989).

    Article  CAS  Google Scholar 

  31. Aoki, K. et al. Comparison of prevalence of chronic atrophic gastritis in Japan, China, Tanzania, and the Dominican Republic. Ann. Epidemiol. 15, 598–606 (2005).

    Article  Google Scholar 

  32. Jacobson, B.C. et al. Who is using chronic acid suppression therapy and why? Am. J. Gastroenterol. 98, 51–58 (2003).

    Article  Google Scholar 

  33. Recker, R.R. Calcium absorption and achlorhydria. N. Engl. J. Med. 313, 70–73 (1985).

    Article  CAS  Google Scholar 

  34. O'Connell, M.B., Madden, D.M., Murray, A.M., Heaney, R.P. & Kerzner, L.J. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am. J. Med. 118, 778–781 (2005).

    Article  CAS  Google Scholar 

  35. Yang, Y.-X., Lewis, J.D., Epstein, S. & Metz, D.C. Long-term proton pump inhibitor therapy and risk of hip fracture. J. Am. Med. Assoc. 296, 2947–2953 (2006).

    Article  CAS  Google Scholar 

  36. Cummings, S.R. & Melton, L.J. Epidemiology and outcomes of osteoporotic fractures. Lancet 359, 1761–1767 (2002).

    Article  Google Scholar 

  37. Straub, D.A. Calcium supplementation in clinical practice: a review of forms, doses, and indications. Nutr. Clin. Pract. 22, 286–296 (2007).

    Article  Google Scholar 

  38. Seitz, S. et al. Paget's disease of bone—histologic analysis of 754 patients. J. Bone Miner. Res. 24, 62–69 (2009).

    Article  Google Scholar 

  39. Parfitt, A.M. et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 2, 595–610 (1987).

    Article  CAS  Google Scholar 

  40. Huebner, A.K. et al. Calcitonin deficiency in mice progressively results in high bone turnover. J. Bone Miner. Res. 21, 1924–1934 (2006).

    Article  CAS  Google Scholar 

  41. Hoff, A.O. et al. Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene. J. Clin. Invest. 110, 1849–1857 (2002).

    Article  CAS  Google Scholar 

  42. Schmidt, K. et al. The high mobility group transcription factor Sox8 is a negative regulator of osteoblast differentiation. J. Cell Biol. 168, 899–910 (2005).

    Article  CAS  Google Scholar 

  43. Amling, M. et al. Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development. J. Cell Biol. 136, 205–213 (1997).

    Article  CAS  Google Scholar 

  44. Simon, R., Mirlacher, M. & Sauter, G. Tissue microarrays. Biotechniques 36, 98–105 (2004).

    Article  CAS  Google Scholar 

  45. Takagi, H., Jhappan, C., Sharp, R. & Merlino, G. Hypertrophic gastropathy resembling Ménétrier's disease in transgenic mice overexpressing transforming growth factor alpha in the stomach. J. Clin. Invest. 90, 1161–1167 (1992).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Amling.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schinke, T., Schilling, A., Baranowsky, A. et al. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med 15, 674–681 (2009). https://doi.org/10.1038/nm.1963

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing