Skip to main content

Advertisement

SpringerLink
Log in

Transient modulation of calcium and parathyroid hormone stimulates bone formation

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Intermittent administration of parathyroid hormone can stimulate bone formation. Parathyroid hormone is a natural hormone that responds to serum calcium levels. In this study, we examined whether a transient increase and/or decrease in the serum calcium can stimulate bone formation. Using a mathematical model previously developed, we first predicted the effects of administration of parathyroid hormone, neutralizing parathyroid hormone antibody, calcium, and EGTA (calcium chelator) on the serum concentration of parathyroid hormone and calcium. The model predicted that intermittent injection of parathyroid hormone and ethylene glycol tetraacetic acid transiently elevated the serum parathyroid hormone, while that of parathyroid hormone antibody and calcium transiently reduced parathyroid hormone in the serum. In vitro analysis revealed that parathyroid hormone’s transient changes (both up and down) elevated activating transcription factor 4-mediated osteocalcin expression. In the mouse model of osteoporosis, both intermittent administration of calcium and ethylene glycol tetraacetic acid showed tendency to increase bone mineral density of the upper limb (ulna and humerus) and spine, but the effects varied in a region-specific manner. Collectively, the study herein supports a common bone response to administration of calcium and its chelator through their effects on parathyroid hormone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. R.C. Gensure, T.J. Gardella, H. Jüppner, Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem. Biophys. Res. Commun. 328, 666–678 (2005)

    Article  CAS  PubMed  Google Scholar 

  2. R.M. Neer, C.D. Arnaud, J.R. Zanchetta, R. Prince, G.A. Gaich, J.Y. Reginster, A.B. Hodsman, E.F. Eriksen, S. Ish-Shalom, H.K. Genant, O. Wang, B.H. Mitlak, Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434–1441 (2001)

    Article  CAS  PubMed  Google Scholar 

  3. A.B. Hodsman, D.C. Bauer, D.W. Dempster, L. Dian, D.A. Hanley, S.T. Harris, D.L. Kendler, M.R. McClung, P.D. Miller, W.P. Olszynski, E. Orwoll, C.K. Yuen, Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr. Rev. 26, 688–703 (2005)

    Article  CAS  PubMed  Google Scholar 

  4. T. Uzawa, M. Hori, S. Ejiri, H. Ozawa, Comparison of the effects of intermittent and continuous administration of human parathyroid hormone(1-34) on rat bone. Bone 16, 477–484 (1995)

    CAS  PubMed  Google Scholar 

  5. H. Dobnig, R.T. Turner, Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 136, 3632–3638 (1995)

    CAS  PubMed  Google Scholar 

  6. J.F. Raposo, A. Pires, H. Yokota, H.G. Ferreira, A mathematical model of calcium and phosphorus metabolism in two forms of hyperparathyroidism. Endocrine 41, 309–319 (2012)

    Article  CAS  PubMed  Google Scholar 

  7. J.F. Raposo, L.G. Sobrinho, H.G. Ferreira, A minimal mathematical model of calcium homeostasis. J. Clin. Endocrinol. Metab. 87, 4330–4340 (2002)

    Article  CAS  PubMed  Google Scholar 

  8. H. Yokota, J.F. Raposo, A. Chen, C. Jiang, H.G. Ferreira, Evaluation of the role of FGF23 in mineral metabolism. Gene Regul. Syst. Biol. 3, 131–142 (2009)

    CAS  Google Scholar 

  9. M.C. Peterson, M.M. Riggs, A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. Bone 46, 49–63 (2010)

    Article  CAS  PubMed  Google Scholar 

  10. P. Tracqui, J.F. Staub, A.M. Perault-Staub, Modelling of in vivo calcium metabolism. II. Minimal structure or maximum dynamic diversity: the interplay of biological constraints. Acta Biotheor. 40, 103–111 (1992)

    Article  CAS  PubMed  Google Scholar 

  11. C.R. Christie, L.E.K. Achenie, B.A. Ogunnaike, A control engineering model of calcium regulation. J. Clin. Endocrinol. Metab. 99, 2844–2853 (2014)

    Article  CAS  PubMed  Google Scholar 

  12. M. Clynes, Unidirectional rate sensitivity: a biocybernetic law of reflex and humoral systems as physiologic channels of control and communication. Ann. N. Y. Acad. Sci. 92, 946–969 (1961)

    Article  CAS  PubMed  Google Scholar 

  13. Y. Imanishi, C. Hall, M. Sablosky, E.M. Brown, A. Arnold, A new method for in vivo analysis of parathyroid hormone-calcium set point in mice. J. Bone Miner. Res. 17, 1656–1661 (2002)

    Article  CAS  PubMed  Google Scholar 

  14. C. Wilczynski, P. Camacho, calcium use in the management of osteoporosis: continuing questions and controversies. Curr. Osteoporos. Rep. 12, 396–402 (2014)

    Article  PubMed  Google Scholar 

  15. B. Dawson-Hughes, S.S. Harris, E.A. Krall, G.E. Dallal, Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N. Engl. J. Med. 337, 670–676 (1997)

    Article  CAS  PubMed  Google Scholar 

  16. S.A. Jamal, S.M. Moe, Calcium builds strong bones, and more is better-correct? Well, maybe not. Clin. J. Am. Soc. Nephrol. 7, 1877–1883 (2012)

    Article  PubMed  Google Scholar 

  17. R.N. Dickerson, L.M. Morgan, M.A. Croce, G. Minard, R.O. Brown, Treatment of moderate to severe acute hypocalcemia in critically ill trauma patients. JPEN. J. Parenter. Enteral Nutr. 31, 228–233 (2007)

    Article  CAS  PubMed  Google Scholar 

  18. M. Silberberg, R. Silberberg, the effects of parathyroid hormone and calcium gluconate on the skeletal tissues of mice*. Am. J. Pathol. 19, 839–859 (1943)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. M.W. Edwards, S.D. Bain, M.C. Bailey, M.M. Lantry, G.A. Howard, 17β Estradiol stimulation of endosteal bone formation in the ovariectomized mouse: an animal model for the evaluation of bone-targeted estrogens. Bone 13, 29–34 (1992)

    Article  CAS  PubMed  Google Scholar 

  20. L.D. Quarles, D.A. Yohay, L.W. Lever, R. Caton, R.J. Wenstrup, Distinct proliferative and differentiated stages of murine MC3T3-E1 cells in culture: an in vitro model of osteoblast development. J. Bone Miner. Res. 7, 683–692 (2009)

    Article  Google Scholar 

  21. K. Hamamura, N. Tanjung, H. Yokota, Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha. J. Bone Miner. Metab. 31, 618–628 (2013)

    Article  CAS  PubMed  Google Scholar 

  22. V. Krishnan, T.L. Moore, Y.L. Ma, L.M. Helvering, C.A. Frolik, K.M. Valasek, P. Ducy, A.G. Geiser, Parathyroid hormone bone anabolic action requires Cbfa1/Runx2-dependent signaling. Mol. Endocrinol. 17, 423–435 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. T. Bellido, A.A. Ali, L.I. Plotkin, Q. Fu, I. Gubrij, P.K. Roberson, R.S. Weinstein, C.A. O’Brien, S.C. Manolagas, R.L. Jilka, Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J. Biol. Chem. 278, 50259–50272 (2003)

    Article  CAS  PubMed  Google Scholar 

  24. T. Matsuura, K. Tokutomi, M. Sasaki, M. Katafuchi, E. Mizumachi, H. Sato, Distinct characteristics of mandibular bone collagen relative to long bone collagen: relevance to clinical dentistry. Biomed Res. Int. 2014, 769414 (2014)

    PubMed  PubMed Central  Google Scholar 

  25. J.A. Clark, G. Schulman, T.A. Golper, Safety and efficacy of regional citrate anticoagulation during 8-hour sustained low-efficiency dialysis. Clin. J. Am. Soc. Nephrol. 3, 736–742 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Edward Berbari for bringing our attention to pupillary responses to light stimulation, and Wenxiao Xu for technical assistance in animal studies. This study was supported in part by the Japan Society for the Promotion of Science Core-to-Core Program, 23003.

Author information

Author notes

    Authors and Affiliations

    1. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA

      Andy B. Chen

    2. Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA

      Kazumasa Minami & Hiroki Yokota

    3. Department of Medical Physics & Engineering Osaka University Graduate School of Medicine Suita, Osaka, Japan

      Kazumasa Minami & Masahiko Koizumi

    4. Department of Public Health, Medical School, New University of Lisbon, Lisbon, Portugal

      João F. Raposo

    5. Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

      Nariaki Matsuura

    6. REQIMTE, Department of Chemistry, New University of Lisbon, Lisbon, Portugal

      Hugo G. Ferreira

    Authors
    1. Andy B. Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Kazumasa Minami
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. João F. Raposo
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Nariaki Matsuura
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Masahiko Koizumi
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Hiroki Yokota
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Hugo G. Ferreira
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Hiroki Yokota.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Andy B. Chen and Kazumasa Minami contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chen, A.B., Minami, K., Raposo, J.F. et al. Transient modulation of calcium and parathyroid hormone stimulates bone formation. Endocrine 54, 232–240 (2016). https://doi.org/10.1007/s12020-016-1066-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12020-016-1066-7

    Keywords

    Search

    Navigation