title: 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.
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.
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kawata
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Imanishi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Onoda
authors.forename: Senji
authors.initials: S
authors.lastname: Okuno
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takemoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Komo
authors.forename: Hideki
authors.initials: H
authors.lastname: Tahara
authors.forename: Michihito
authors.initials: M
authors.lastname: Wada
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nagano
authors.forename: Eiji
authors.initials: E
authors.lastname: Ishimura
authors.forename: Takami
authors.initials: T
authors.lastname: Miki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inaba
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nishizawa
mesh_terms: D000069449:Cinacalcet; D006801:Humans; D049950:Hyperparathyroidism, Primary; D006962:Hyperparathyroidism, Secondary; D007150:Immunohistochemistry; D009281:Naphthalenes / Q000494:pharmacology*; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D016105:Parathyroidectomy; D018167:Receptors, Calcitriol / Q000032:analysis; D044169:Receptors, Calcium-Sensing / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism
chemical_list: D009281:Naphthalenes; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D000069449:Cinacalcet