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Single‐cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism
Author(s) -
Koh James,
Hogue Joyce A.,
Wang Yuli,
DiSalvo Matthew,
Allbritton Nancy L.,
Shi Yuhong,
Olson John A.,
Sosa Julie A.
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12732
Subject(s) - calcium , primary hyperparathyroidism , hyperparathyroidism , extracellular , biology , calcium metabolism , parathyroid chief cell , calcium sensing receptor , endocrinology , medicine , adenoma , parathyroid hormone , microbiology and biotechnology
Primary hyperparathyroidism ( PHPT ) is a common endocrine neoplastic disorder caused by a failure of calcium sensing secondary to tumour development in one or more of the parathyroid glands. Parathyroid adenomas are comprised of distinct cellular subpopulations of variable clonal status that exhibit differing degrees of calcium responsiveness. To gain a clearer understanding of the relationship among cellular identity, tumour composition and clinical biochemistry in PHPT , we developed a novel single cell platform for quantitative evaluation of calcium sensing behaviour in freshly resected human parathyroid tumour cells. Live‐cell intracellular calcium flux was visualized through Fluo‐4‐ AM epifluorescence, followed by in situ immunofluorescence detection of the calcium sensing receptor ( CASR ), a central component in the extracellular calcium signalling pathway. The reactivity of individual parathyroid tumour cells to extracellular calcium stimulus was highly variable, with discrete kinetic response patterns observed both between and among parathyroid tumour samples. CASR abundance was not an obligate determinant of calcium responsiveness. Calcium EC 50 values from a series of parathyroid adenomas revealed that the tumours segregated into two distinct categories. One group manifested a mean EC 50 of 2.40 mM (95% CI : 2.37–2.41), closely aligned to the established normal range. The second group was less responsive to calcium stimulus, with a mean EC 50 of 3.61 mM (95% CI : 3.45–3.95). This binary distribution indicates the existence of a previously unappreciated biochemical sub‐classification of PHPT tumours, possibly reflecting distinct etiological mechanisms. Recognition of quantitative differences in calcium sensing could have important implications for the clinical management of PHPT .

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