Regulation of parathyroid hormone gene expression and peptide secretion in human parathyroid cells

In cell cultures prepared from human parathyroid adenomas, parathyroid hormone (PTH) mRNA expression decreased slowly. During short-term incubations (less than 24 h), a low calcium concentration (0.5 mmol/l) and protein kinase C activator TPA (12-O-tetradecanoyl phorbol 13-acetate) (160 nmol/l) increased PTH secretion (60%; p < 0.05), while a high extracellular calcium concentration (2.5 mmol/l) reduced PTH secretion (60%; p < 0.05). The TPA could block the inhibitory effect of a high calcium level on PTH peptide secretion. All these agents had no effect on PTH mRNA accumulation in short-term experiments. In long-term cultures (more than 24 h), a low calcium level increased and a high calcium level reduced both PTH mRNA (85 and 34%; p < 0.05) and peptide secretion (140 and 80%; p < 0.05), respectively. The TPA reduced PTH mRNA accumulation down to 30% (p < 0.05) and PTH secretion down to 14% (p < 0.05) in a time- and dose-dependent fashion. The TPA also reversed the stimulatory effect of hypocalcemia on PTH mRNA accumulation and peptide secretion. Protein kinase C inhibitors staurosporine (100 nmol/l) and H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride) (50 mumol/l) had similar effects to TPA on PTH gene expression and peptide secretion in long-term cultures. The results support the hypothesis that extracellular calcium regulates PTH mRNA accumulation and PTH secretion via protein kinase C.