Secondary hyperparathyroidism is characterized by an increase in parathyroid (PT) cell number, and parathyroid hormone (PTH) synthesis and secretion. It is still unknown as to what stimuli regulate PT cell proliferation and how they do this. We have studied rats with dietary-induced secondary hyper-and hypoparathyroidism, rats given 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and rats after 5/6 nephrectomy for the presence of PT cell proliferation and apoptosis. PT cell proliferation has been measured by staining for proliferating cell nuclear antigen (PCNA) and apoptosis by in situ detection of nuclear DNA fragmentation and correlated with serum biochemistry and PTH mRNA levels. A low calcium diet led to increased levels of PTH mRNA and a 10-fold increase in PT cell proliferation. A low phosphate diet led to decreased levels of PTH mRNA and the complete absence of PT cell proliferation. 1,25(OH)2D3 (25 pmol/d x 3) led to a decrease in PTH mRNA levels and unlike the hypophosphatemic rats there was no decrease in cell proliferation. There were no cells undergoing apoptosis in any of the experimental conditions. The secondary hyperparathyroidism of 5/6 nephrectomized rats was characterized by an increase in PTH mRNA levels and PT cell proliferation which were both markedly decreased by a low phosphate diet. The number of PCNA positive cells was increased by a high phosphate diet. Therefore hypocalcemia, hyperphosphatemia and uremia lead to PT cell proliferation, and hypophosphatemia completely abolishes this effect. Injected 1,25(OH)2D3 had no effect.These findings emphasize the importance of a normal phosphate and calcium in the prevention of PT cell hyperplasia. (J. Clin. Invest. 1995. 96:1786-1793.) Key words: parathyroid hormone * apoptosis* hyperplasia * 1,25(OH)2D3 chronic renal failure.

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The expression of the PTH and calcitonin genes is dramatically decreased by 1,25(OH)2D3 in vivo, and the PTH gene expression is increased by hypocalcemia. We have now studied the effect of estrogens on the expression of these genes in vivo.

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Background. Mutated p53 acts as a dominant oncogene, whereas the wild type (wt) p53 gene product suppresses cell growth. Abnormalities in the p53 gene are reported in more than 50% of malignant tumors. Recently, an allelic loss of chromosome 17p, where the p53 gene is located, was found to be more frequent in hepatocellular carcinoma (HCC) cell lines and human tumors. In addition, in half of the cases of HCC from endemic areas for hepatitis B virus and aflatoxin, a hot spot point mutation at codon 249 was detected, as previously reported. Missense mutations in p53, mdm‐2 complex formation, and other unknown mechanisms may lead to stabilization of the gene product, thus rendering it detectable by immunohistochemistry. Methods. To assess the relationship between p53 status at a premalignant stage and in HCC, the authors studied the immunohistologic expression of p53 in HCC and in the adjacent nontumorous resected liver tissue, using monoclonal antibody to wt and mutated p53. Results. Twelve of the 14 patients with liver tumors had HCC. Of the 12 patients with HCC and underlying cirrhosis, 8 (67%) had increased p53 expression in HCC cells. Eight of the 12 patients with p53‐positive HCC cells tad p53 overexpression in the nontumorous hepatocytes within regenerative nodules adjacent to HCC tissue. Three of 21 cirrhotic livers without a detectable tumor had increased p53 expression in the regenerative nodules. None of the 12 patients with chronic active hepatitis without cirrhosis or the 13 with a normal liver histology had increased p53 expression. Conclusion. p53 overexpression in some cirrhotic livers and in nontumorous livers of patients with HCC may indicate a normal p53 gene response to cellular stress or, alternatively, to an abnormally or mutated p53 gene, and could occur before the development of HCC.