Skip to main content

Advertisement

SpringerLink
Log in

Cinacalcet HCl Suppresses Cyclin D1 Oncogene-Derived Parathyroid Cell Proliferation in a Murine Model for Primary Hyperparathyroidism

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Cinacalcet HCl (cinacalcet) is a calcimimetic compound, which suppresses parathyroid (PTH) hormone secretion from parathyroid glands in both primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). We previously reported the suppressive effect of cinacalcet on PTH secretion in vivo in a PHPT model mouse, in which parathyroid-targeted overexpression of the cyclin D1 oncogene caused chronic biochemical hyperparathyroidism and parathyroid cell hyperplasia. Although cinacalcet suppressed parathyroid cell proliferation in SHPT in 5/6-nephrectomized uremic rats, its effect on PHPT has not yet been determined. In this study, the effect of cinacalcet on parathyroid cell proliferation was analyzed in PHPT mice. Cinacalcet (1 mg/g) was mixed into the rodent diet and orally administrated to 80-week-old PHPT mice for 10 days before death. 5-Bromo-2′-deoxyuridine (BrdU, 6 mg/day) was infused by an osmotic pump for 5 days before death, followed by immunostaining of the thyroid–parathyroid complex using an anti-BrdU antibody to estimate parathyroid cell proliferation. Compared to untreated PHPT mice, cinacalcet significantly suppressed both serum calcium and PTH. The proportion of BrdU-positive cells to the total cell number in the parathyroid glands increased considerably in untreated PHPT mice (9.5 ± 3.1%) compared to wild-type mice (0.7 ± 0.1%) and was significantly suppressed by cinacalcet (1.2 ± 0.2%). Cinacalcet did not affect apoptosis in the parathyroid cells of PHPT mice. These data suggest that cinacalcet suppressed both serum PTH levels and parathyroid cell proliferation in vivo in PHPT.

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. Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM, Arnold A (1991) A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350:512–515

    Article  PubMed  CAS  Google Scholar 

  2. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ (1997) Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–407

    Article  PubMed  CAS  Google Scholar 

  3. Imanishi Y, Tahara H (2001) Putative parathyroid tumor suppressor on 1p: independent molecular mechanisms of tumorigenesis from 11q allelic loss. Am J Kidney Dis 38:S165–S167

    Article  PubMed  CAS  Google Scholar 

  4. Imanishi Y, Hosokawa Y, Yoshimoto K, Schipani E, Mallya S, Papanikolaou A, Kifor O, Tokura T, Sablosky M, Ledgard F, Gronowicz G, Wang TC, Schmidt EV, Hall C, Brown EM, Bronson R, Arnold A (2001) Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 107:1093–1102

    Article  PubMed  CAS  Google Scholar 

  5. Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, Brown EM, Seidman JG, Seidman CE (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11:389–394

    Article  PubMed  CAS  Google Scholar 

  6. Imanishi Y, Inaba M, Kawata T, Nishizawa Y (2009) Animal models of hyperfunctioning parathyroid diseases for drug development. Expert Opin Drug Discov 4:727–740

    Article  CAS  Google Scholar 

  7. Kifor O, Moore FD Jr, Wang P, Goldstein M, Vassilev P, Kifor I, Hebert SC, Brown EM (1996) Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 81:1598–1606

    Article  PubMed  CAS  Google Scholar 

  8. Gogusev J, Duchambon P, Hory B, Giovannini M, Goureau Y, Sarfati E, Drueke TB (1997) Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 51:328–336

    Article  PubMed  CAS  Google Scholar 

  9. Brown AJ, Ritter CS, Finch JL, Slatopolsky EA (1999) Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate. Kidney Int 55:1284–1292

    Article  PubMed  CAS  Google Scholar 

  10. Kawata T, Imanishi Y, Kobayashi K, Onoda N, Okuno S, Takemoto Y, Komo T, Tahara H, Wada M, Nagano N, Ishimura E, Miki T, Ishikawa T, Inaba M, Nishizawa Y (2006) Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels. J Bone Miner Metab 24:300–306

    Article  PubMed  CAS  Google Scholar 

  11. Block GA, Martin KJ, de Francisco AL, Turner SA, Avram MM, Suranyi MG, Hercz G, Cunningham J, Abu-Alfa AK, Messa P, Coyne DW, Locatelli F, Cohen RM, Evenepoel P, Moe SM, Fournier A, Braun J, McCary LC, Zani VJ, Olson KA, Drueke TB, Goodman WG (2004) Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350:1516–1525

    Article  PubMed  CAS  Google Scholar 

  12. Lindberg JS, Culleton B, Wong G, Borah MF, Clark RV, Shapiro WB, Roger SD, Husserl FE, Klassen PS, Guo MD, Albizem MB, Coburn JW (2005) Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. J Am Soc Nephrol 16:800–807

    Article  PubMed  CAS  Google Scholar 

  13. Messa P, Macario F, Yaqoob M, Bouman K, Braun J, von Albertini B, Brink H, Maduell F, Graf H, Frazao JM, Bos WJ, Torregrosa V, Saha H, Reichel H, Wilkie M, Zani VJ, Molemans B, Carter D, Locatelli F (2008) The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. Clin J Am Soc Nephrol 3:36–45

    Article  PubMed  CAS  Google Scholar 

  14. Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M (2003) The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 88:5644–5649

    Article  PubMed  CAS  Google Scholar 

  15. Wada M, Furuya Y, Sakiyama J, Kobayashi N, Miyata S, Ishii H, Nagano N (1997) The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest 100:2977–2983

    Article  PubMed  CAS  Google Scholar 

  16. Colloton M, Shatzen E, Miller G, Stehman-Breen C, Wada M, Lacey D, Martin D (2005) Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int 67:467–476

    Article  PubMed  CAS  Google Scholar 

  17. Kawata T, Imanishi Y, Kobayashi K, Kenko T, Wada M, Ishimura E, Miki T, Nagano N, Inaba M, Arnold A, Nishizawa Y (2005) Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism. Eur J Endocrinol 153:587–594

    Article  PubMed  CAS  Google Scholar 

  18. Mizobuchi M, Ogata H, Hatamura I, Saji F, Koiwa F, Kinugasa E, Koshikawa S, Akizawa T (2007) Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells. Biochem Biophys Res Commun 362:11–16

    Article  PubMed  CAS  Google Scholar 

  19. Imanishi Y, Inaba M, Kawata T, Nishizawa Y (2009) Cinacalcet in hyperfunctioning parathyroid diseases. Ther Apher Dial 13(Suppl 1):S7–S11

    Article  PubMed  CAS  Google Scholar 

  20. Wettschureck N, Lee E, Libutti SK, Offermanns S, Robey PG, Spiegel AM (2007) Parathyroid-specific double knockout of Gq and G11 α-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+-sensing receptor. Mol Endocrinol 21:274–280

    Article  PubMed  CAS  Google Scholar 

  21. Weber K, Bergow C, Hirmer S, Schuler C, Erben RG (2009) Vitamin D-independent therapeutic effects of extracellular calcium in a mouse model of adult-onset secondary hyperparathyroidism. J Bone Miner Res 24:22–32

    Article  PubMed  CAS  Google Scholar 

  22. Mizobuchi M, Hatamura I, Ogata H, Saji F, Uda S, Shiizaki K, Sakaguchi T, Negi S, Kinugasa E, Koshikawa S, Akizawa T (2004) Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency. J Am Soc Nephrol 15:2579–2587

    Article  PubMed  CAS  Google Scholar 

  23. Mendoza FJ, Lopez I, Canalejo R, Almaden Y, Martin D, Aguilera-Tejero E, Rodriguez M (2009) Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats. Am J Physiol Renal Physiol 296:F605–F613

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Edward F. Nemeth and Dr. Karen J. Krapcho (NPS Pharmaceuticals) for providing us with the 4638 CaR polyclonal antibody. This work was supported in part by Grants-in-Aid for Scientific Research (C) (20591101 to Y. I., 20590980 to M. I. and Y. I.), a research grant from the Osaka Kidney Foundation (OKF07-0003 to Y. I.), and the JOS Distinguished Paper Award from the Japan Osteoporosis Society.

Author information

Authors and Affiliations

  1. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Yasuo Imanishi, Takehisa Kawata & Masaaki Inaba

  2. Pharmacological Research Laboratories, Research Division, Kyowa Hakko Kirin Co, Shizuoka, Japan

    Takehisa Kawata, Michihito Wada & Nobuo Nagano

  3. Osaka City University Medical School for Technical Assistance, Osaka City University Graduate School of Medicine, Osaka, Japan

    Takao Kenko

  4. Department of Geriatrics and Neurology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Takami Miki

  5. Center for Molecular Medicine, University of Connecticut School of Medicine, Farmington, CT, USA

    Andrew Arnold

Authors
  1. Yasuo Imanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takehisa Kawata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takao Kenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michihito Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nobuo Nagano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takami Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrew Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masaaki Inaba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuo Imanishi.

Additional information

The authors have stated that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Imanishi, Y., Kawata, T., Kenko, T. et al. Cinacalcet HCl Suppresses Cyclin D1 Oncogene-Derived Parathyroid Cell Proliferation in a Murine Model for Primary Hyperparathyroidism. Calcif Tissue Int 89, 29–35 (2011). https://doi.org/10.1007/s00223-011-9490-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-011-9490-4

Keywords

Search

Navigation