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Direct in Vitro Evidence of Extracellular Ca²⁺-Induced Amino-Terminal Truncation of Human Parathyroid Hormone (1–84) by Human Parathyroid Cells

Departments of Metabolism, Endocrinology, and Molecular Medicine (T.K., Y.I., K.K., H.T., M.I., Y.N.), Oncology (N.O.), Urology (Y.T.), Nephrology (E.I.), Geriatrics and Neurology (T.M.), and Surgical Oncology (T.I.), Osaka City University Graduate School of Medicine, Osaka 545-8585; and Shirasagi Hospital (S.O.), Osaka 546-0002, Japan

Address all correspondence and requests for reprints to: Yasuo Imanishi, M.D., Ph.D., 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. E-mail: imanishi{at}med.osaka-cu.ac.jp.

Context: Although serum calcium (Ca²⁺) concentration regulates the generation of amino-terminally (N-terminally) truncated forms of human PTH (hPTH) degraded from (1–84)hPTH, no studies have yet reported whether the parathyroid gland itself is responsible for this process.

Objective: Our objective was to determine the site of N-terminal truncation and its roles in PTH metabolism in parathyroid cells in vitro.

Methods: The effect of extracellular Ca²⁺ concentration was examined on N-terminal truncation in primary cultured parathyroid cells. The parathyroid glands were obtained from the patients with primary and uremia-associated secondary hyperparathyroidisms who underwent therapeutic parathyroidectomies.

Results: The N-terminally truncated fragments were detectable with commercially available intact PTH (I-PTH) assays, but not with the bio-intact PTH (Bio-PTH) assay, which detected only the (1–84)hPTH. HPLC revealed that generation of N-terminally truncated fragments detectable by I-PTH increased with extracellular Ca²⁺ concentration. Suppression of PTH secretion by increasing the extracellular Ca²⁺ concentration was more evident with the Bio-PTH assay than with the I-PTH assay for both cultured parathyroid cells prepared from parathyroid adenomas and uremia-associated secondary hyperparathyroidism. The Bio-PTH/I-PTH ratio, which is the ratio of (1–84)hPTH to the sum of (1–84)hPTH and N-terminally truncated fragments, decreased in response to increases in extracellular Ca²⁺.

Conclusions: These findings suggest that the N-terminal truncation is regulated by extracellular Ca²⁺ concentration and works to suppress the generation of (1–84)hPTH in parathyroid cells.

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