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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

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Abstract

Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT). However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of cinacalcet on PTH secretion was analyzed in primary cultured parathyroid cells obtained from patients. The investigation involved three PHPT and three SHPT patients subjected to therapeutic parathyroidectomy. Notably, all SHPT patients were resistant to intravenous vitamin D analogue therapy. Removed parathyroid tumors were used for immunohistochemistry and parathyroid cell primary culture. Immunohistochemical analyses revealed diminished expression of CaR and vitamin D receptor (VDR) in all parathyroid tumors. PTH secretion from cultured parathyroid cells of PHPT and SHPT patients was suppressed by extracellular Ca2+ and cinacalcet in a dose-dependent manner. Rates of suppression of PTH secretion in PHPT and SHPT by cinacalcet (1000 nmol/l) were 61% ± 21% and 61% ± 19%, respectively. Cinacalcet demonstrates significant potency in the suppression of PTH secretion in primary cultured human parathyroid cells in vitro, despite reduced levels of the target protein, CaR. Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy.

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Authors and Affiliations

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

    Takehisa Kawata, Yasuo Imanishi, Keisuke Kobayashi, Takeshi Komo, Hideki Tahara, Masaaki Inaba & Yoshiki Nishizawa

  2. Department of Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Naoyoshi Onoda

  3. Shirasagi Hospital, Osaka, Japan

    Senji Okuno

  4. Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Yoshiaki Takemoto

  5. Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd., Takasaki, Japan

    Takehisa Kawata, Michihito Wada & Nobuo Nagano

  6. Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Eiji Ishimura

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

    Takami Miki

  8. Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Tetsuro Ishikawa

Authors
  1. Takehisa Kawata
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  2. Yasuo Imanishi
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  3. Keisuke Kobayashi
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  4. Naoyoshi Onoda
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  8. Hideki Tahara
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  9. Michihito Wada
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  10. Nobuo Nagano
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  11. Eiji Ishimura
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  12. Takami Miki
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  13. Tetsuro Ishikawa
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  14. Masaaki Inaba
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  15. Yoshiki Nishizawa
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Corresponding author

Correspondence to Yasuo Imanishi.

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Kawata, T., Imanishi, Y., Kobayashi, K. et al. 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 (2006). https://doi.org/10.1007/s00774-006-0687-y

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  • DOI: https://doi.org/10.1007/s00774-006-0687-y

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